Adverse experience occurred with a high frequency in a longterm (greater than 3 years), prospective, double blind, followed by an open trial of methotrexate (MTX) therapy in 45 patients with rheumatoid arthritis (RA). Adverse experiences occurred in 96% of patients, and the discontinuation rate was 44% over 176 weeks. No hepatic or pulmonary fibrosis occurred. Unusual toxicities included weight loss (2 patients), systemic fungal infections (2 patients), and transient noncirrhotic ascites (1 patient). Baseline white blood cell counts and creatinine may help predict adverse experiences. The full dose-toxicity spectrum of MTX RA is not yet fully defined.