OBJECTIVES: To conduct a German economic evaluation of natalizumab compared to other disease modifying drugs (DMD) in relapsing-remitting Multiple Sclerosis (MS) from a societal perspective METHODS: A Markov model was designed to compare costs and outcomes of Natalizumab (Nb), other DMD (interferon-beta, glatiramer acetate) and best supportive care (BSC). The expanded disability status scale (EDSS) and the line of treatment were used to define the distinctive Markov States. Transition probabilities for progression, treatment switches and withdrawals were derived from clinical studies and literature. German real-life treatment data of MS-patients under DMD were collected retrospectively (N=554) and used to validate assumptions and conduct sensitivity analyses. Cost data and quality of life estimates were taken from a European burden of MS study. A time horizon of 30 years and annual discount rates of 3% for costs and outcomes were chosen .  RESULTS: Treatment with Nb resulted in 8.13 avoided relapses over 30 years, and in 2.36 avoided relapses under other DMD. After 30 years, the proportion of surviving patients at a low state of disease (incl. EDSS 4) was 59% for the Nb group, 31% for the other DMD and 8% for patients in the BSC group. The average MS related costs over 30 years were estimated at €847,160 for Nb, €816,139 for other DMD, and €627,701 for BSC. Cost per quality adjusted life year (QALY) was €60,938 for Nb, €64,481 for other DMD and €53,911 for BSC. The incremental cost effectiveness of Nb compared to other DMD was €24,919 per QALY. CONCLUSIONS: MS is a resource intense disease due to its chronic course and its severe impact on patients’ daily life. Long term analysis suggests that even treatment without DMD is expensive and leads to considerable inferior clinical outcomes. Treatment with DMD improves the situation of patients, with Natalizumab showing the highest efficacy and best cost-effectiveness ratio.