OBJECTIVES: To estimate relapse-associated cost savings due to reduction in MS-related hospitalization rates among natalizumab patients with relapsing multiple sclerosis (MS), including those with highly-active disease. METHODS: A probabilistic model was developed to estimate natalizumab-associated cost savings based on reductions in annualized MS-related hospitalization rates due to relapse. Hospitalization rate data were obtained from the randomized, double-blind, placebo-controlled, phase 3, natalizumab monotherapy clinical trial (AFFIRM). Among the 942 patients with relapsing MS who received natalizumab 300 mg (n=627) or placebo (n=315) intravenously for up to 116 weeks, those who reported ≥2 relapses in the prior year and ≥1 Gd+ enhancing lesions were considered highly-active (n=148 for natalizumab, n=61 for placebo). Natalizumab reduced the annualized MS-related hospitalization rate by 65% (p<0.001) among all patients (0.034 natalizumab vs 0.097 placebo) and by 89% (p<0.001) among those with highly-active disease (0.015 natalizumab vs 0.137 placebo). Cost savings associated with such reductions were assessed using MS hospitalization costs obtained from a random sample of the PharMetrics database ($19,750/episode, 2007 US Dollars). The model ran 1,000 simulations to estimate the mean costs of MS hospitalizations and associated 95% confidence intervals (CI). RESULTS: Due to relapse-associated hospitalization rate reductions, the 2-year per-patient MS hospitalization cost was $1,338 (95%CI: $842, $1964) for natalizumab and $3828 (95%CI: $2628, $5281) for placebo, resulting in a cost savings of $2490 (95%CI: $1,143, $3980). In patients with highly-active disease, the 2-year per-patient MS hospitalization cost was $604 (95%CI: $86, $1643) for natalizumab and $5436 (95%CI: $2558, $9593) for placebo, resulting in a cost savings of $4832 (95%CI: $1988, $9111). CONCLUSIONS: Natalizumab significantly reduced relapse-associated costs of MS-related hospitalizations in patients with relapsing MS, with the magnitude of reduction being even larger among those with highly-active disease.