OBJECTIVES: Clinical trials establishing the efficacy of disease modifying drugs (DMDs) utilized in treating relapsing forms of Multiple Sclerosis (MS) have been based on populations of varying baseline relapse rates and disability burden. It is the objective of this model to be used as a tool to compare the relative cost-effectiveness (CE) of these drugs from a payer perspective. METHODS: An interactive Excel-based model was developed to compare the relative cost components of relapses, disability progression, and DMDs in the treatment of MS. Drug effectiveness with respect to reduction in relapses and the slowing of disability progression was derived from the published Level I clinical trial data and was based on absolute risk reduction (ARR) in clinical events to account for differences between study populations. Cost data was based on work by O'Brien and colleagues, and disability progression data was based on research by Weinshenker and colleagues. Drug costs were based on wholesale acquisition cost with consideration of contractual discounts and patient co-payment. The primary economic endpoint was cost per relapse avoided over a 4-year period of treatment. RESULTS: The ARR varied across the five DMDs with interferon beta-1a SC injection (Rebif®) showing the highest results (0.72) and interferon beta-1a IM injection (Avonex®) the lowest (0.26). Economic results showed significant difference in the cost-effectiveness ratio (CER) among the DMDs, with interferon beta-1a SC injection (Rebif®) having the most favorable CER (US$47958/relapse avoided) and interferon beta-1a IM injection (Avonex®) having the least favorable (US$121,147/relapse avoided). Interferon beta-1b SC injection (Betaseron®), glatiramer acetate SC injection (Copaxone®), and natalizumab IV injection (Tysabri®) offer intermediate CER results of US$48,345, US$68,440, and US$93,903 per relapse avoided, respectively. CONCLUSION: Modeling absolute reduction in clinical endpoints provides a methodology for comparing clinical trials and demonstrates that the difference in cost-effectiveness results among the DMDs is significant.