OBJECTIVES: The aim of this meta-analysis was to evaluate the efficacy and tolerability of Natalizumab in relapsing multiple sclerosis (MS). METHODS:  “Mean change in Expanded Disability Status Scale (EDDS)”, “number of patients with at least one relapse”, and “number of patients with at least one new gadolinium (Gd)-enhancing lesion” were the key outcomes of interest for assessment of efficacy. “Any adverse events”, “serious adverse events”, “death”, and “withdrawal because of adverse events” were the key outcomes for tolerability. RESULTS: Amongst existing trials, four randomized placebo controlled clinical trials met our criteria and were included. Pooled Relative Risk for at least one relapse in four trials including all doses was 0.7, a non-significant RR (95% CI: 0.42-1.17, P=0. 17). Summary RR for at least one relapse in two trials in which doses of 3 mg/kg or 6mg/kg or 300 mg every 4 weeks were administered gave a values of 0.5 as a significant RR (95% CI: 0.42-0.61, P<0.0001). The summary RR for at least one new Gd-enhancing lesion was 0.22, a non-significant RR (95% CI: 0.05-1.01, P= 0.051). Three deaths were reported in natalizumab group. Comparing adverse events between natalizumab and placebo yielded a non significant RR of 0.99 (95% CI: 0.96-1.01, P= 0.34) for any adverse events (n=3), and a significant RR of 0.39 (95% CI: 0.29-0.52, P<0.0001) for serious adverse events (n=2). A summary RR for withdrawal due to adverse events by natalizumab vs. placebo therapy between two trials was 1.43, a non-significant RR (95% CI: 0.68-3.02, P= 0.35). CONCLUSIONS: It seems that using 3 mg/kg or 6 mg/kg every four weeks is the best experienced method of administration of natalizumab for preventing relapse and occurrence of new Gd-enhancing. Further clinical trials are still needed.