OBJECTIVES: To assess the cost-effectiveness of disease modifying therapies (DMTs) alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate (Glatopa®, Copaxone® 20mg), interferon beta-1a (30mcg, 22mcg, 44mcg), interferon beta-1b (Betaseron®, Extavia®), natalizumab, peginterferon beta-1a, teriflunomide (7mg, 14mg) in relapsing-remitting multiple sclerosis (RRMS) in the US. METHODS: We used a lifetime Markov model from a US payer perspective with health states based on Kurtzke Expanded Disability Status Scale (EDSS) in RRMS and secondary-progressive MS. RRMS patients with mean age 29 entered the model with EDSS 0-6. Relative risks of EDSS progression and rate ratios for relapses for each DMT compared to supportive care were based on a network meta-analysis of clinical trials. Safety and discontinuation data were summarized from trials. Published data was used for cost by EDSS, cost per relapse, and utilities. Discounted wholesale acquisition costs were used for DMT costs. Outcomes were projected life-years, quality-adjusted life-years (QALYS), relapses, cost per QALY (ICER), and cost per relapse-avoided. RESULTS: Projected life-years and QALYS ranged from 21.9 and 7.8 for teriflunomide 7mg to 23.1 and 12.6 for alemtuzumab, relapses ranged from 15.6 for interferon beta-1a (Avonex®) to 10.8 for alemtuzumab, and total costs ranged from $572,000 for alemtuzumab to $1,480,100 for daclizumab. Alemtuzumab dominated all other DMTs for both ICER and cost per relapse-avoided. In the absence of alemtuzumab, glatiramer acetate (Glatopa®), interferon beta-1a (Extavia®), peginterferon beta-1a, natalizumab, and daclizumab increased QALYs compared to supportive care, with resulting ICERs of $194,300, $148,300, $11,939,400, $284,200, and $309,600, respectively; and glatiramer acetate (Glatopa®), dimethyl fumarate, fingolimod, and natalizumab decreased relapses compared to supportive care, with resulting costs per relapse-avoided of $261,200, $3,269,000, $120,600, and $119,300, respectively. CONCLUSIONS: Alemtuzumab provided the best health outcomes and lowest costs for patients with RRMS.