The safety and efficacy of mesalamine enemas were determined ina dose-ranging study enrolling 287 patients with ulcerative proctitis and proctosigmoiditis in a double-blind, placebo-controlled, multicenter trial. Patients were randomized to receive placebo, 1, 2, or 4 g in 100 ml mesalamine (PENTASA) enemas h.s. for 8 weeks. Efficacy was assessed by clinical, sigmoidoscopic, and histologic improvement, as well as by induction of remission. Sixty-seven percent, 65%, and 75% of patients receiving 1-, 2-, and 4-g enemas were markedly improved according to the physician's global assessment compared with 27% of patients treated with placebo. The mean improvement in sigmoidoscopic index was 5.8, 5.9, and 6.4 points (on a 15-point scale) for the 1-, 2-, and 4-g enema groups compared with a decrease of 1.8 points for the placebo group. Improvement in biopsy scores was observed in 47, 55, and 59% of 1-, 2-, and 4-g groups contrasted with 27% of the placebo-treated patients. All three doses were significantly more effective than placebo in reducing symptoms and trips to the toilet compared with placebo. No dose-response relation was demonstrated. The safety profile was similar to that of placebo. In conclusion, mesalamine enemas are effective as a single agent in the short-term treatment of distal ulcerative colitis without an apparent dose response between 1 and 4 g nightly.