An increasing amount of clinical data indicates that low-dose methotrexate therapy for rheumatoid arthritis is both effective and free of serious side effects. Since 1967 we treated 78 patients with definite or classic rheumatoid arthritis who showed inadequate response to conventional therapy. Up to 15 mg of methotrexate was given weekly by the intramuscular route. Morning stiffness, severity of pain at rest and with activity, extent of active synovitis, functional capacity, change in steroid dosage, complete blood count, erythrocyte sedimentation rate, and gamma glutamyl transpeptidase were monitored. Overall assessment indicated that 45 of the 78 (58 percent) patients showed marked improvement or complete remission, usually within four weeks. When maximum improvement was obtained, most patients were switched to oral therapy with a variable degree of success, and dosage was decreased as tolerated. No serious toxicity was noted. In 34 patients a total of 67 liver biopsy specimens were obtained, some after as long as 15 years of therapy. Minor changes observed are the same as in patients with rheumatoid arthritis not treated with methotrexate. Because the risks did not appear justified, routine annual biopsies were discontinued. In contrast to other cytotoxic drugs, no carcinogenesis has been demonstrated with methotrexate. It appears that methotrexate is approximately as effective as intramuscular gold and D-penicillamine but that it has a quicker onset of response and less serious toxicity.