OBJECTIVES: Natalizumab is a new disease-modifying therapy (DMT) for the treatment of relapsing multiple sclerosis (MS). A model was designed to determine the relative cost-effectiveness of natalizumab compared with the other four currently available disease-modifying therapies (intramuscular [IM] interferon beta [IFNß]-1a, IFNß-1b, glatiramer acetate [GA], and subcutaneous [SC] IFNß-1a) for the treatment of relapsing MS in the United States. METHODS: Analyses were conducted from a managed care perspective with a time horizon of 2 years (first 2 years after initiation of therapy). Model inputs were drug acquisition costs, costs of drug administration and monitoring, costs of treating relapses, and anticipated reduction in relapse rates. Outcomes included total 2-year costs per patient and costs per relapse avoided for each therapy. Number of relapses avoided was calculated as the weighted average number of relapses for placebo-treated patients (1.90) multiplied by the anticipated relapse rate reduction for each therapy (natalizumab, 67%; IM IFNß-1a, 32%; IFNß-1b, 34%; GA, 29%; and SC IFNß-1a, 32%). Cost per relapse avoided was calculated as the total 2-year cost of therapy divided by the number of relapses avoided over 2 years. RESULTS: The overall 2-year cost of therapy per patient was $67,037 for natalizumab, $42,311 for IM IFNß-1a, $44,680 for IFNß-1b, $44,300 for GA, and $46,373 for SC IFNß-1a. The cost per relapse avoided was lowest for natalizumab at $52,605 followed by $69,091 for IFNß-1b, $69,517 for IM IFNß-1a, $76,191 for SC IFNß-1a, and $80,314 for GA. Model inputs with the most influence on cost per relapse avoided for natalizumab were weighted average number of relapses prior to treatment and anticipated relative reduction in relapse rate. CONCLUSION: Although the drug acquisition cost of natalizumab was higher than that of the other DMTs, it was the most cost-effective therapy as measured by total cost per relapse avoided.