OBJECTIVES: To assess the cost-effectiveness of natalizumab (NAT) as first-line treatment of Highly-Active Relapsing-Remitting Multiple Sclerosis (HARRMS) versus pooled interferon-beta (IFN) and glatiramer acetate (GA) from the Brazilian Public Healthcare (SUS) perspective. Natalizumab is currently only reimbursed for RRMS patients that failed therapy with IFN and GA. Currently, no guidance exist for patients with HARRMS in Brazil. METHODS: A microsimulation model was developed with yearly cycles over a 20-year time horizon.  Four different treatment sequences are included in the model: T1=NAT-IFN-GA, T2=NAT-GA-IFN, T3=IFN-GA-NAT and T4=GA-IFN-NAT, allowing treatment failures [i.e., >=1-point increase in the Expanded Disability Status Scale (EDSS)] to alternate therapies. Patients may experience EDSS progression, relapses, remain stable, discontinue treatment, or die. Natural history was parameterized from the 2005 UK MS Survey. Efficacy, utilities and safety/discontinuation data were derived from respective pivotal trials. HARRMS was defined as >2 disabling relapses in previous year and >1 gadolinium-enhancing lesions or a significant increase in T2 lesions. Direct costs were from government reimbursement lists (i.e., DATASUS, BPS, SIGTAP), discounted at 5% yearly, and reported in Brazilian currency (1BRL=0.35USD). Consequences were assessed in quality adjusted life years (QALY). Monte-Carlo first-order was used. RESULTS: Natalizumab as first-line for HARRMS (sequences T1 and T2) was considered cost-effective in comparison to sequences T3 and T4 (standard practice). Total costs (K=thousands) and QALYs for each treatment arm were: T4=BRL187K/5.43QALY, T3=BRL203K/5.41QALY, T2=BRL227K/7.02QALY and T1=BRL228K/7.01QALY. The incremental cost-effectiveness ratio (ICER) for T1 and T2 relative to the least costly sequence (T4) were BRL25,258/QALY and BRL26,324/QALY respectively, and considered acceptable assuming a threshold of 3x the national gross domestic product (GDP) per capita (~BRL70,000/QALY).  CONCLUSIONS: Since patients with HARRMS experience higher relapse rates and faster disability progression than the general RRMS population, natalizumab as first-line option is cost-effective and brings additional benefits to Brazilian patients.