Objectives To assess the efficacy and safety of synthetic disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis (RA)-a first step in a European League Against Rheumatism (EULAR) initiative to produce recommendations for the management of RA. Methods A systematic review of the literature using PubMed, Embase and the Cochrane library was performed up to January 2009. All randomised controlled trials (RCTs) reporting the efficacy of synthetic DMARDs (vs placebo or other synthetic DMARDs) on signs and symptoms, disability and/or radiographic structural damage in patients with RA were selected. Studies of biological agents or glucocorticoids were excluded. A pooled effect size (ES) was calculated by meta-analysis. Safety and the occurrence of infections and neoplasia was also assessed. Results 97 RCTs (14 159 patients) were analysed for efficacy. The pooled analysis indicated that methotrexate (MTX) was more efficacious in reducing signs and symptoms, disability and radiographic structural damage than other synthetic DMARDs pooled: ES for swollen joint count (SJC) versus pooled DMARDs = 1.42 (95% CI 0.65 to 2.18). Leflunomide appeared to be as effective as MTX. Sulfasalazine and injectable gold were efficacious in reducing signs and symptoms and structural damage. Ciclosporin, minocycline, tacrolimus and hydroxychloroquine showed some efficacy in reducing SJC. Auranofin and D-penicillamine showed no significant superiority over placebo. The risks of cancer and of infection were increased with cyclophosphamide and azathioprine. Conclusions MTX was well-tolerated and effective in reducing signs and symptoms, disability and structural damage. A comparison with other synthetic DMARDs was in favour of MTX, though at the tested doses MTX and leflunomide were equally effective.