Cyclophosphamide in high doses was given for six months to 19 patients with rheumatoid arthritis. A second group of patients with rheumatoid arthritis whose conditions were stable on low-dose prednisone received in addition either cyclophosphamide or placebo for six months. Measurements of joint function and joint inflammation were used to estimate disease activity. Joint inflammation progressively decreased and joint function improved in the high-dose group. The low-dose cyclophosphamide-plus-prednisone group had a similar response that was different from the prednisone-plus-placebo group. Cyclophosphamide toxicity was common in the high-dose group and minimal in the low-dose-plus-prednisone group. Cyclophosphamide therapy improved the arthritis of these patients. The results were almost as good in the low-dose-plus-prednisone group, and the toxicity was much less.