OBJECTIVES: Multiple sclerosis (MS) is a neurologic disease that can dramatically affect the patient. The aim of this study is to conduct a cost-effectiveness analysis of natalizumab (Tysabri®) versus interferon beta-1a (IFNB1a) 44mcg (Rebif®) for treating Highly Active Relapsing Remitting Multiple Sclerosis (HARRMS) patients. IFNB1a 44mcg was chosen as comparator since it is the most widely prescribed disease modifying therapy for 1st-line treatment in HARRMS patients in Brazil.  METHODS: We developed a Markov model with 20-year time horizon comparing natalizumab to IFNB1a 44mcg. Health states were based on EDSS and relapses (moderate or severe). Since there are no published data evaluating long-term course specifically in HARRMS, we assumed transition probabilities on EDSS states based on natural history studies on unselected RRMS patients, and relapse probabilities based on a post-hoc analysis of the pivotal natalizumab AFFIRM trial. This is a rather conservative approach, since disability progression may be slower in this proposed model then expected for patients with HARRMS and so the benefit from natalizumab could be underappreciated. In each monthly cycle, patients can discontinue treatment, remain stable, progress to higher EDSS state, experience Progressive Multifocal Leukoencephalopathy or die. Patients with EDSS score≥7.5 receive best supportive care. Resource use and costs were validated by an expert’s panel and valued using Brazilian public official lists (DATASUS and BPS). Costs and outcomes were discounted (5%). Probabilistic sensitivity analyses (PSA) covered variability in efficacy and costs. RESULTS: Use of natalizumab was associated with slower EDSS progression and reduced relapse burden. Life years gained with natalizumab and IFNB1a 44mcg were 10.90 and 10.54, and costs were USD119,977 and USD132,446, respectively. In the base-case, natalizumab was dominant versus IFNB1a 44mcg. PSA has confirmed the consistency of results. CONCLUSIONS: For a patient with HARRMS, the model shows that natalizumab was dominant when compared to IFNB1a 44mcg in the Brazilian Public Healthcare System.