Forty-two patients with active rheumatoid arthritis were studied serially with respect to glucose metabolism after the institution of different anti-inflammatory and antirheumatic therapies. Sixteen patients received 20 mg of prednisolone daily. After 1 week of treatment the mean k value in glucose tolerance tests increased from 1.0 +/- 0.1 (SEM) to 1.6 +/- 0.1 (P less than .001). The corticosteroid therapy thus restored the glucose tolerance to normal and significantly enhanced the insulin response (P less than .01). Corticosteroids also normalized the growth hormone response to glucose infusion but had no effect on plasma glucagon. Treatment with nonsteroidal anti-inflammatory drugs did not affect the k values nor the hormonal pattern either after short-term treatment or after three months of therapy, except for causing a minor increase in the plasma glucagon levels both before and after glucose infusion. The long-term effects of treatment with penicillamine (n = 4), chloroquine (n = 7), and immunosuppressive agents [corticosteroids combined with azathioprine or cyclophosphamide (n = 7)], were an improvement of the clinical state, a reduction of the inflammatory activity, and a reversal of the glucose handling to normal.