As filed with the Securities and Exchange Commission on June 28, 2006

Registration No. 333-133021

UNITED STATES SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

Amendment No. 4

to

FORM S-1

REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933

REPLIDYNE, INC.

(Exact name of registrant as specified in its charter)

1450 Infinite Dr.

Louisville, CO 80027

(303) 996-5500

(Address, including zip code, and telephone number, including area code, of registrant’s principal executive offices)

Kenneth J. Collins

President and Chief Executive Officer

Replidyne, Inc.

1450 Infinite Dr.

Louisville, CO 80027

(303) 996-5500

(Name, address, including zip code, and telephone number, including area code, of agent for service)

Copies to:

         Approximate date of commencement of proposed sale to the public: As soon as practicable after the effective date of this registration statement.

         If any of the securities being registered on this form are to be offered on a delayed or continuous basis pursuant to Rule 415 under the Securities Act, check the following box.    o

         If this form is filed to register additional securities for an offering pursuant to Rule 462(b) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.    o                            

         If this form is a post-effective amendment filed pursuant to Rule 462(c) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.    o                            

         If this form is a post-effective amendment filed pursuant to Rule 462(d) under the Securities Act, check the following box and list the Securities Act registration number of the earlier effective registration statement for the same offering.    o                            

         If delivery of the prospectus is expected to be made pursuant to Rule 434, check the following box.    o                            

         The Registrant hereby amends this Registration Statement on such date or dates as may be necessary to delay its effective date until the Registrant shall file a further amendment that specifically states that this Registration Statement shall thereafter become effective in accordance with Section 8(a) of the Securities Act of 1933, as amended, or until the Registration Statement shall become effective on such date as the Commission, acting pursuant to said Section 8(a), may determine.

P R O S P E C T U S (Subject to Completion)

Issued June 28, 2006

4,500,000 Shares

Common Stock

          We are offering 4,500,000 shares of our common stock. This is our initial public offering and no public market currently exists for our shares. We anticipate that the initial public offering price will be $10.00 per share.

          Our common stock has been approved for quotation on the Nasdaq National Market under the symbol “RDYN,” subject to official notice of issuance.

          Investing in our common stock involves risks. See “Risk Factors” beginning on page 7.

PRICE $           A SHARE

          We have granted the underwriters the right to purchase up to an additional 675,000 shares of common stock from us at the public offering price, less the underwriting discounts and commissions to cover over-allotments.

          The Securities and Exchange Commission and state securities regulators have not approved or disapproved these securities, or determined if this prospectus is truthful or complete. Any representation to the contrary is a criminal offense.

          The underwriters expect to deliver the shares to purchasers on or about                , 2006.

TABLE OF CONTENTS

          You should rely only on the information contained in this prospectus. We have not, and the underwriters have not, authorized anyone to provide you with information different from or in addition to that contained in this prospectus. If anyone provides you with different or inconsistent information, you should not rely on it. We are offering to sell, and are seeking offers to buy, shares of common stock only in jurisdictions where offers and sales are permitted. The information contained in this prospectus is accurate only as of the date of this prospectus, regardless of the time of delivery of this prospectus or of any sale of the common stock. Our business, financial conditions, results of operations and prospects may have changed since that date.

          For investors outside the U.S.: Neither we nor any of the underwriters have done anything that would permit this offering or possession or distribution of this prospectus in any jurisdiction where action for that purpose is required, other than in the U.S. You are required to inform yourselves about and to observe any restrictions relating to this offering and the distribution of this prospectus.

          Through and including                     , 2006 (25 days after the date of this prospectus), all dealers that buy, sell or trade our common stock, whether or not participating in this offering, may be required to deliver a prospectus. This delivery requirement is in addition to the obligation of dealers to deliver a prospectus when acting as underwriters and with respect to their unsold allotments or subscriptions.

	•	Maximize commercial potential for Orapem as a leading community antibiotic and a preferred branded oral beta-lactam in adult and pediatric markets.
	•	Develop specialty sales and marketing capabilities to target specialist physicians in major metropolitan areas, including otolaryngologists, if Orapem is approved for adult use, and pediatricians, if Orapem is approved for pediatric use. We plan to leverage this sales force to market other products that we may develop, acquire or in-license.
	•	Develop REP8839/mupirocin combination for topical use in treatment of skin and wound infections and prevention of S. aureus infections, including MRSA infections, in hospital settings.
	•	Discover and develop novel anti-infective products by continuing to pursue our discovery research programs in DNA replication inhibition and our program to develop a treatment for C. difficile.
	•	Leverage our development, regulatory and commercial resources by acquiring or in-licensing additional products or product candidates.

Common stock offered by us		4,500,000 shares
Common stock to be outstanding after this offering		26,426,497 shares
Use of proceeds		To fund clinical trials and other research and development activities; to fund activities in preparation for the potential commercial launch of Orapem; and for working capital, capital expenditures and other general corporate purposes.
Nasdaq National Market symbol		RDYN

	•	1,779,318 shares of common stock issuable upon the exercise of outstanding options, with a weighted average exercise price of $3.11 per share;
	•	111,375 shares of common stock reserved for future issuance under our benefit plans; and
	•	53,012 shares of common stock issuable upon the exercise of outstanding warrants, with a weighted average exercise price of $5.47 per share.

	•	a 1-for-4.904 reverse stock split of our common stock effected on June 26, 2006.
	•	the conversion of all our outstanding shares of preferred stock into 18,067,322 shares of common stock;
	•	the issuance of 1,781,826 shares of common stock to the holders of our Series A, B, C and D convertible preferred stock upon the closing of this offering in satisfaction of accumulated dividends, as required by the terms of the Series A, B, C and D convertible preferred stock, assuming for this purpose that the closing of this offering occurs on July 3, 2006 and the initial public offering price is $10.00 per share, all of which is described more fully under the section of this prospectus entitled “Capitalization;”
	•	the filing of our restated certificate of incorporation, which will occur immediately prior to the closing of this offering; and
	•	no exercise of the underwriters’ over-allotment option.

																Three Months Ended
				Year Ended December 31,												March 31,
				2003				2004				2005				2005				2006
																(unaudited)				(unaudited)
				(in thousands, except share and per share amounts)
Statement of Operations Data:
Revenue				$	726			$	834			$	441			$	267			$	2,877
Costs and expenses:
	Research and development				12,331				16,282				29,180				5,013				8,970
	Sales, general and administrative				2,155				2,994				5,329				686				1,953
		Total costs and expenses			14,486				19,276				34,509				5,699				10,923
		Loss from operations			(13,760	)			(18,442	)			(34,068	)			(5,432	)			(8,046	)
Other (expense) income, net					(190	)			(797	)			399				42				344
		Net loss			(13,950	)			(19,239	)			(33,669	)			(5,390	)			(7,702	)
Preferred stock dividends and accretion					(1,294	)			(3,560	)			(7,191	)			(1,291	)			(2,653	)
Net loss attributable to common stockholders				$	(15,244	)		$	(22,799	)		$	(40,860	)		$	(6,681	)		$	(10,355	)
Basic and diluted net loss attributable to common stockholders per share(1):
	Historical			$	(20.82	)		$	(30.55	)		$	(39.20	)		$	(8.13	)		$	(7.21	)
	Pro forma											$	(2.18	)						$	(0.37	)
Weighted average shares outstanding(1):
	Historical				732,044				746,306				1,042,388				821,757				1,435,726
	Pro forma												15,414,638								21,015,376

		As of March 31, 2006
						Pro Forma
		Actual				As Adjusted
		(in thousands)
Balance Sheet Data:
Cash, cash equivalents and short-term investments		$	109,900			$	150,150
Working capital			98,800				139,050
Total assets			116,112				156,362
Accumulated deficit			(93,060	)			(93,060	)
Preferred stock			139,568				—
Total stockholders’ (deficit) equity			(92,539	)			87,279

(1)	Please see Note 1 to our financial statements for an explanation of the method used to calculate the historical and pro forma net loss attributable to common stockholders per share and the number of shares used in the computation of the per share amounts.

RISK FACTORS

          You should carefully consider the risks described below, which we believe are the material risks of our business and this offering, before making an investment decision. Our business could be harmed by any of these risks. The trading price of our common stock could decline due to any of these risks, and you may lose all or part of your investment. In assessing these risks, you should also refer to the other information contained in this prospectus, including our financial statements and related notes.

Risk Related to our Business

We are dependent on the success of our lead product candidate, Orapem, and we cannot give any assurance that it will receive regulatory approval, which is necessary before it can be commercialized.

          If we are not able to commercialize Orapem, we will not generate product revenues for several years, if at all, and we may never generate sufficient revenue to achieve and sustain profitability. We need approval from the FDA prior to marketing our product candidates in the U.S. In December 2005, we submitted our first NDA to the FDA for use of Orapem in four clinical indications, and the FDA accepted this NDA for filing in February 2006. Even if we obtain FDA approval for Orapem, it may not cover all of the clinical indications for which we are seeking approval and we expect that the FDA will likely require additional clinical trials, including a placebo-controlled trial in the case of acute exacerbation of chronic bronchitis. Also, an approval might contain significant limitations with respect to conditions of use in the form of narrow indications, warnings, precautions or contra-indications. We cannot predict if or when we might seek regulatory review of Orapem for any other indications or of any of our other product candidates.

          The FDA has substantial discretion in the approval process and may either refuse to accept an application for substantive review or may conclude after review of our data that our application is insufficient to allow approval of a product candidate. If the FDA does not accept or approve our application, it may require that we conduct additional clinical, pre-clinical or manufacturing validation studies and submit that data before it will reconsider our application. Depending on the extent of these or any other studies, approval of any application that we submit may be delayed by several years, or may require us to expend more resources than we have available. It is also possible that additional studies, if performed and completed, may not be considered sufficient by the FDA to approve our application or any particular indication for which we are seeking approval. If any of these outcomes occur, we may be forced to abandon our application for approval, which might cause us to cease operations.

          Our lead product candidate, Orapem, has been in-licensed from another pharmaceutical company, Daiichi Asubio Pharma Co., Ltd., or Daiichi Asubio. A previous licensee, Bayer AG, or Bayer, completed extensive pre-clinical studies and Phase II and Phase III clinical trials for a particular dosage of Orapem. We are relying on the data from these pre-clinical studies and clinical trials in our application to the FDA for approval to market Orapem. Any problems with these previous pre-clinical studies or clinical trials, including problems with the design or statistical analysis of such pre-clinical studies or clinical trials, could cause our application for regulatory approval to be delayed or rejected, in which case we might need to conduct additional trials. In addition, because these clinical trials were conducted using an active compound manufactured by Nippon Soda Co., Ltd., or Nippon Soda, at its facility in Takaoka, Japan, we expect the FDA will require us to demonstrate to its satisfaction the comparability of the active compound we are sourcing from Nippon Soda’s new facility in Nihongi, Japan.

The FDA may change its approval policies or requirements, or apply interpretations to its policies or requirements, in a manner that could delay or prevent commercialization of Orapem for some or all indications that are the subject of our pending NDA.

          Regulatory requirements for approval of antibiotics may change in a manner that requires us to conduct additional large-scale clinical trials, which may delay or prevent commercialization of Orapem for some or all indications. Historically, the FDA and foreign regulatory authorities have not required placebo-

controlled clinical trials for approval of antibiotics but instead have relied on non-inferiority studies. In a non-inferiority study, a drug candidate is compared with an approved antibiotic treatment and it must be shown that the product candidate is not less effective than the approved treatment. All efficacy studies upon which our NDA is based were designed as non-inferiority studies after consultation with the FDA. In September 2005, the FDA indicated to us that it will likely require data from a placebo-controlled trial of Orapem before it will consider approving it for acute exacerbation of chronic bronchitis. In May 2006, the FDA requested an explanation of how our non-inferiority studies contained in our NDA for Orapem support efficacy in each of the indications for which we are seeking approval. We cannot assure you that the FDA will not require placebo-controlled trials, or other trials involving comparator antibiotics, to demonstrate the superiority of Orapem to placebo before considering the approval of Orapem for one or more of the indications that are the subject of our pending NDA. Conducting placebo-controlled trials for antibiotics can be time consuming and expensive and can be difficult to complete. Institutional review boards may not grant approval for placebo-controlled trials because of ethical concerns about denying some participating patients access to any antibiotic therapy during the course of the trial. It may be difficult to enroll patients in placebo-controlled trials even if institutional review board approval is obtained because certain patients would receive no therapy. Although we are currently conducting a placebo-controlled trial for acute exacerbation of chronic bronchitis, we have not completed any placebo-controlled trials for Orapem for any indications. We may not be able to show a statistically significant advantage over placebo in any trials that we are able to complete. These factors could delay for several years or ultimately prevent commercialization of Orapem for any indications for which the FDA requires placebo-controlled trials.

          The efficacy of Orapem in subjects with uncomplicated skin and skin structure infections was evaluated in two Phase III studies. The results of one study met the protocol-specified criterion for non-inferiority of Orapem to amoxicillin/clavulanate. A second study did not demonstrate non-inferiority of Orapem to cephalexin. The FDA has informed us that evidence based on only a single trial will not provide adequate evidence for efficacy for this indication. Therefore, unless the FDA accepts our pooled clinical data compiled in two studies, we will likely need to complete additional trials in order to obtain approval for this indication. Even if we complete these additional trials, we may not be able to obtain adequate evidence of efficacy to support approval in uncomplicated skin and skin structure infections.

We may experience significant delays in the launch of Orapem for commercialization, which in turn could delay or prevent us from generating significant revenues from the sale of Orapem products.

          We could experience potentially significant delays in the commercial launch of Orapem due to many factors, such as:

Any one or a combination of these events could significantly delay or prevent our ability to commercialize Orapem. If we are not successful in commercializing Orapem, or are significantly delayed in doing so, our business will be materially harmed.

The success of Orapem depends heavily on our collaboration with Forest Laboratories, which was established only in February 2006 and involves a complex sharing of decisions, responsibilities, costs and benefits. Any loss of Forest Laboratories as a partner, or any adverse developments in the collaboration, would materially harm our business.

          In February 2006, we entered into a collaboration agreement with Forest Laboratories to develop and commercialize Orapem. We have granted Forest Laboratories an exclusive sublicense for the development and sale of Orapem for all indications in the U.S. We have also granted Forest Laboratories a right of first refusal to extend the territory to include Canada. Forest Laboratories is responsible for funding a substantial portion of the continued development of Orapem, including clinical trials and regulatory approval. If the FDA approves Orapem, Forest Laboratories will also have primary responsibility for the marketing and sales of the approved product and will share responsibility for compliance with regulatory requirements.

          Although Forest Laboratories has an established sales force targeting primary care physicians, they do not have significant experience marketing antibiotics. We have limited control over the amount and timing of resources that Forest Laboratories will dedicate to the development, approval and marketing of Orapem. Although we share decision-making authority with respect to the marketing of Orapem through a joint marketing committee, Forest Laboratories generally has the right to make final decisions on this committee if the parties are unable to reach consensus.

          We are subject to a number of additional risks associated with our dependence on our collaboration with Forest Laboratories, including:

          Forest Laboratories could also fail to effectively manage its manufacturing relationship with its supplier of Orapem tablets, Tropon GmbH, or Tropon, or with our supplier of Orapem drug substance, Nippon Soda. Forest Laboratories is contractually bound to purchase all of its tablet requirements from Tropon, subject to certain exceptions. Tropon and Nippon Soda will be subject to ongoing periodic unannounced inspections by the FDA and corresponding state agencies for compliance with good manufacturing practices regulations, or cGMPs, and similar foreign standards. Neither we nor Forest Laboratories has control over compliance by Tropon and Nippon Soda with these regulations and standards.

          Furthermore, Forest Laboratories may terminate our collaboration agreement upon our material breach of the collaboration agreement or our bankruptcy. Forest Laboratories may also terminate our agreement upon 90 days’ notice in the event that Forest Laboratories reasonably determines the development program indicates issues of safety or efficacy that are likely to prevent or significantly delay the filing or approval of an NDA for Orapem or to result in labeling or indications that would significantly adversely affect the marketing of any product developed under the agreement.

          We do not currently have the resources necessary to develop and market Orapem on our own. If either we or Forest Laboratories do not perform our respective obligations under, or devote sufficient resources to, our collaboration, or if we and Forest Laboratories do not work effectively together, Orapem may not be successfully commercialized. If our collaboration were to be terminated, we would need to establish an alternative collaboration and may not be able to do so on acceptable terms or at all.

We are at an early stage of development as a company, with limited sources of revenue, and we may never become profitable.

          We are a development stage biopharmaceutical company with a limited operating history. Currently, we have no products approved for commercial sale and, to date, we have not generated any revenue from product sales. Our ability to generate revenue depends heavily on:

          Our existing product candidates will require extensive additional clinical evaluation, regulatory approval, significant marketing efforts and substantial investment before they can provide us with any revenue. If we do not receive regulatory approval for and successfully commercialize Orapem, we will be unable to generate any revenue from product sales for many years, if at all. If we are unable to generate revenue, we will not become profitable, and we may be unable to continue our operations.

We have incurred significant operating losses since inception and anticipate that we will incur continued losses for the foreseeable future.

          We have experienced significant operating losses since our inception in 2000. At December 31, 2005, we had a deficit accumulated during the development stage of approximately $83.1 million. We have generated no revenue from product sales to date. We have funded our operations to date principally from the sale of our securities and from payments by Forest Laboratories under our collaboration agreement. We expect to continue to incur substantial additional operating losses for the next several years as we pursue our clinical trials and research and development efforts. Because of the numerous risks and uncertainties associated with developing and commercializing antibiotics, we are unable to predict the extent of any future losses. We may never have any significant future revenue or become profitable.

The commercial success of our product candidates will depend upon attaining significant market acceptance of these products among physicians, patients, health care payors and the medical community.

          None of our product candidates has been commercialized for any indication. Even if approved for sale by the appropriate regulatory authorities, physicians may not prescribe our product candidates, in which case we would not generate revenue or become profitable. Market acceptance of our lead product candidate, Orapem, and any future product candidates by physicians, healthcare payors and patients will depend on a number of factors, including:

If our product candidates are unable to compete effectively with generic and branded antibiotics, our commercial opportunity will be reduced or eliminated.

          If approved, our lead product candidate, Orapem, will compete against both generic and branded community antibiotic therapies. The market for such products is very competitive and includes generic products, such as amoxicillin/clavulanate, and established branded products, such as Omnicef, Zithromax, Ketek and Levaquin, which are marketed by major pharmaceutical companies, all of which have significantly greater financial resources and expertise in research and development, pre-clinical testing, conducting clinical trials, obtaining regulatory approvals, manufacturing and marketing approved products than we do. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large, established companies.

          Over the next several years, our products will face more competition in the form of generic versions of branded products of competitors that will lose their patent exclusivity. For example, Orapem will begin to face competition from generic Omnicef in 2008. Generic antibiotic therapies typically are sold at lower prices than branded antibiotics and are preferred by managed care providers of health services. If we are unable to demonstrate to physicians that, based on experience, clinical data, side-effect profiles and other factors, our products are preferable to these generic antibiotic therapies, we may never generate meaningful revenue. Our commercial opportunity will also be reduced or eliminated if our competitors develop and commercialize generic or branded antibiotics that are safer, more effective, have fewer side effects or are less expensive than our product candidates.

          Daiichi Asubio owns a portfolio of patents related to faropenem compounds, including the faropenem parent compound, Orapem and other faropenem prodrugs. We have licensed from Daiichi Asubio the patents to Orapem and other faropenem prodrugs. These patents may not prevent competitors from developing other faropenem drugs that are not covered by the Daiichi Asubio patents. Beginning in