OBJECTIVES: To determine the cost-effectiveness of all drugs recommended in Portugal for the treatment of highly active relapsing multiple sclerosis, using as the effectiveness measure, the time to first relapse published in clinical or observational long-term studies. METHODS: An Excel patient level simulation model was developed to determine the time on treatment for a population of high disease activity patients, using the time to first relapse observed in the literature for MAVENCLAD^®, natalizumab and fingolimod, over a 4-year period. Costs were obtained from Portuguese data sources. RESULTS: In a 10.000 Monte Carlo simulation of high disease activity patients, MAVENCLAD^®, natalizumab and fingolimod resulted in average costs per day until relapse of 40,48€, 45,20 € and 52,19€, respectively. In the model MAVENCLAD^® generated additional days without relapse of 124,36 vs fingolimod and 5,68 vs natalizumab, with savings of 7.550,99 € and 5.403,75 €, respectively, over a 4-year period. Also, when comparing against each other, natalizumab generated additional 118,68 days vs fingolimod with savings of 2.147,23 €. CONCLUSIONS: In the current model MAVENCLAD^® dominates both natalizumab and fingolimod, generating additional days without relapse at a lower cost than both alternatives. Natalizumab dominates fingolimod.