A comparative trial of the effectiveness of 5-azacytidine, azathioprine and prednisolone in patients with rheumatoid arthritis. We treated 34 patients with active rheumatoid arthritis for 5 weeks with 5-azacytidine (50 mg) orally t.i.d.; azathioprine (1 mg/kg) orally daily; and prednisolone (15 mg) orally daily. The course of the disease was evaluated in each patient by assessment of the disease severity and frequency. No significant improvement was observed in the group receiving prednisolone, while a significant improvement was observed in the group receiving 5-azacytidine and azathioprine. The difference between the effects of azathioprine and 5-azacytidine, or azathioprine and prednisolone was not significant. When the groups were classified by disease severity at entry to the trial, a highly significant improvement was noted in the mildly affected group when treated with azathioprine or 5-azacytidine, but not when treated with prednisolone. In the severely affected group, no significant improvement was observed in any of the three treatment groups. No side effects were reported during the trial. The results support the suggestion that 5-azacytidine and azathioprine should be considered as alternative antirheumatic drugs.