OBJECTIVES: Using long-term follow-up data from clinical trials, this analysis assesses the cost-effectiveness of five treatment strategies in patients diagnosed with relapsing-remitting multiple sclerosis (RRMS): symptom management alone (SMA) and symptom management combined with subcutaneous glatiramer acetate (SCGA), intramuscular interferon beta-1-a (IM-IFNβ1-a), subcutaneous interferon beta-1-a (SC-IFNβ1-a), or subcutaneous interferon beta-1-b (SC-IFNβ1-b). METHODS: A literature-based Markov model was developed to assess the cost-effectiveness of five treatment strategies for managing a hypothetical cohort of patients diagnosed with RRMS in the United States (US). Health states were based on the Kurtzke expanded disability status scale (EDSS) (higher EDSS scores = increased disease severity). Relapse and disease progression transition probabilities for SMA were obtained from natural history studies. Treatment effects of the immunomodulatory therapies were estimated by applying a percent reduction to the SMA transition probabilities and adjusting for neutralizing antibodies (NAbs) and treatment discontinuation. Therapy-specific data was obtained from clinical trials and long-term follow-up studies. Transitions among health states occurred in 1-month cycles for the lifetime of a patient. Costs (2005US$) and outcomes were discounted at 3% annually. RESULTS: The incremental cost per quality-adjusted life-year (QALY) is $258,465, $303,008, $395,686, and $310,691 for SCGA, IM-IFNβ1-a, SC-IFNβ1-a and SC-IFNβ1-b compared to SMA respectively. Sensitivity analyses showed results were sensitive to changes in utilities, disease progression rates, time horizon and immunomodulatory therapy cost. CONCLUSIONS: Model results indicated that the immunomodulatory therapies are both more effective and more costly than SMA in treating RRMS. Although the reported incremental cost-effectiveness ratios (ICERs) are well above $50,000/QALY, not all economic evaluations are bounded by this threshold and numerous interventions with ICERs above this threshold have been deemed valuable by patients, health care decision-makers and society. This model suggests that of the immunomodulatory therapies for MS SCGA is the most cost-effective.