OBJECTIVES: To assess the relative efficacy and safety of high (HD) and low dose (LD) beta interferons (IFNβ-1a and FNβ-1b) and glatiramer treatments in relapsing-remitting multiple sclerosis. METHODS: Systematic review of literature. A bibliography search was carried out to identify primary studies on MEDLINE and EMBASE until February 2011. Other databases consulted were: Cochrane library, Centre for Reviews and Dissemination, ECRI, ISI Web of Knowledge e INHATA. Inclusion criteria: 1) head to head randomized clinical trials; 2) patients with relapsing-remitting multiple sclerosis; and 3) Outcomes: relapse rate, proportion of relapse-free patients, time to first relapse, expanded disability status scale, magnetic resonance imaging outcomes and adverse effects. A quality assessment was carried out to estimate the internal validity of the selected studies and the quality of their evidence. Indirect comparison were analysed when head to head studies weren’t available. RESULTS: Eight studies were included in this report, 5 head to head studies between HD and LD IFNβ and 3 studies which compared the HD beta interferons with glatiramer. No studies were found which compared LD beta interferon and glatiramer. The included studies had moderate internal validity. Direct comparison between the three beta interferons LD 1-a, HD1-a and HD1-b showed that all of them were effective and HD IFNβ were better than LD IFNβ. There was weak indirect and direct evidence for similar efficacy between the HD IFNβ. The comparison HD interferons and glatiramer did not show significant differences in their relapse rate and MRI measures. CONCLUSIONS: 1) HD interferons showed greater efficacy at short term in reducing relapses than low-dose interferon. Currently, the estimation of the relative efficacy of two high-dose interferons is not possible but there is weak evidence in favor of similar efficacy, and 2) HD interferons and glatiramer showed similar efficacy for relapse measures at 2 years.