Leflunomide, the newest disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis (RA), inhibits de novo pyrimidine biosynthesis. In two placebo-controlled trials, leflunomide was superior to placebo and comparable to sulphasalazine and methotrexate for improving the signs and symptoms of RA, significantly improved functional ability compared with placebo, sulphasalazine and methotrexate, and was superior to methotrexate and comparable to sulphasalazine in slowing radiographically assessed disease progression. In a multinational trial vs methotrexate, leflunomide showed an American College of Rheumatology (ACR) response rate similar to that in placebo-controlled trials. The ACR response rate with methotrexate was significantly greater. Differences between these trials included methotrexate dosing regimens, folate usage and disease duration. Common adverse events with leflunomide included gastrointestinal symptoms, allergic reactions, alopecia and elevated liver enzyme levels. No long-term safety issues were reported with leflunomide at 2 yr. Efficacy of leflunomide was maintained at 2 yr. Leflunomide is a safe and efficacious addition to the roster of anti-rheumatic drugs.