This double-blind, randomized study investigated the role of oxygen-derived free radical scavengers in the management of recurrent attacks of ulcerative colitis. To this end, allopurinol (50 mg four times a day) and dimethyl sulfoxide (500 mg four times a day) were administered orally. Patients with recurrent attacks of moderate proctosigmoidal ulcerative colitis, in spite of prophylaxis with orally administered sulfasalazine (2 gm daily), were given 10 mg prednisolone by mouth four times a day; 500 mg sulfasalazine by mouth four times a day; and morning and evening retention steroid enema (Predsol, 20 mg) alone or with allopurinol or dimethyl sulfoxide. After 2 weeks of treatment with sulfasalazine and prednisolone alone, 51% of patients (n = 45) were free of symptoms. Addition of allopurinol (n = 46) or dimethyl sulfoxide (n = 45) to the mentioned regimen controlled the symptoms within 2 weeks in 84% of patients (p less than 0.01). During 12 months of prophylactic treatment, 5% of patients (n = 42) who were given sulfasalazine (2 gm daily) and allopurinol and 5% of patients (n = 40) who were given sulfasalazine (2 gm daily) and dimethyl sulfoxide relapsed compared with 25% of patients who were given sulfasalazine (2 gm daily) alone (p less than 0.05). The results suggest that oxygen-derived free radicals may be involved in the mechanism of ulcerative colitis and that removing them may be useful in the treatment of attacks and in protecting the colon against recurrence of attacks.