The aims of this study were to assess the efficacy and safety of rituximab in patients with active rheumatoid arthritis (RA). The authors surveyed randomized controlled trials (RCTs) that examined the efficacy of rituximab in disease modifying anti-rheumatic drug (DMARD) (including methotrexate [MTX]) or tumor necrosis factor (TNF)-blocker-resistant or intolerant patients with active RA using Medline, the Cochrane Controlled Trials Register, and manual searches. Meta-analysis of RCTs was performed to determine the treatment efficacy and safety outcomes of rituximab (1 course, consisting of two infusions of 1,000 mg each) concomitant with MTX. The three RCTs included 938 DMARD or TNF-blocker-resistant or intolerant RA patients. Follow-up periods ranged from 24 to 48 weeks. American College of Rheumatology response (ACR) 20, ACR50, and ACR70 response rates were significantly higher for the rituximab plus MTX than for placebo controls (primary efficacy outcome, ACR50; risk ratio [RR] 3.648, 95% confidence interval [CI] 2.478-5.369, P < 0.001). For those treated with rituximab, the incidence adverse events of all systems were not higher than in those treated with placebo (RR 1.062, 95% CI 0.912-1.236, P = 0.438). With respect to the number of patients that experienced at least one serious adverse event, no significant difference was observed between patients treated with rituximab and placebo (RR 0.855, 95% CI 0.622-1.174, P = 0.333). A single course of rituximab with concomitant MTX therapy was found to be effective in DMARD or TNF-blocker-resistant or intolerant patients with active RA.