OBJECTIVES: To assess the cost-utility of oral fingolimod (Gilenya) versus IV natalizumab (Tysabri) in active relapsing remitting multiple sclerosis (RRMS) from Belgian healthcare (RIZIV/INAMI + patient), governmental and societal perspectives. METHODS: A 40-year Markov model was developed containing 20 health states describing disability severity based upon the Expanded Disability Status Scale (EDSS): 10 RRMS EDSS states (0-9), 10 secondary progressive MS (SPMS) EDSS states (0-9) and a death state. Per annual cycle, RRMS patients can remain stable, progress to a higher RRMS EDSS state or convert to SPMS at a higher EDSS state. Patients have a fixed annual probability of relapse and death (national age-adjusted mortality). RRMS patients with EDSS score <6.5 are eligible for disease modifying therapies (DMTs). Patients with SPMS or EDSS score ≥ 6.5 receive best supportive care. Transition probabilities were based on the natural history of RRMS and the relative risk of confirmed disability progression and relapse per DMT. Efficacy of natalizumab (AFFIRM) and fingolimod (FREEDOMS) was based upon indirect comparison with adjustment for differences in baseline disease characteristics and demographics. Belgian costs and utilities obtained from literature were assigned to each EDSS level and to relapse. DMT monitoring and administration costs were based upon expert opinion. Costs (3%) and outcomes (1.5%) were discounted. Probabilistic sensitivity analyses covered variability in efficacy, costs and utilities. RESULTS: Base-case analyses revealed cost-effectiveness of fingolimod from the health care perspective and dominance from governmental and societal perspective. The probability of fingolimod being cost-effective (<35,000€/QALY) varied between 64% and 70%. Results were sensitive to the hazard ratio of disability progression due to wide and overlapping confidence intervals (indirect treatment comparison). Excluding uncertainty in this parameter resulted in probabilities of cost-effectiveness between 81% and 100%. CONCLUSIONS: Treatment of active RRMS with fingolimod was cost-effective from all payers’ perspectives versus treatment with natalizumab.