High-dose aspirin therapy for rheumatoid arthritis is frequently associated with severe gastrointestinal injury. To explore the possibility of reversing such damage, we conducted a double-blind, multicenter study with misoprostol, a prostaglandin E1 analog, which has demonstrated mucosal protective, gastric antisecretory, and ulcer healing properties. We also studied possible interference of misoprostol with continuing aspirin treatment in the management of patients with rheumatoid arthritis. Patients with confirmed rheumatoid arthritis and endoscopically documented gastroduodenal lesions were randomly assigned to receive 200 μg of misoprostol four times a day (123 patients) or placebo (116 patients). Each concurrently received 650 to 1300 mg of aspirin four times a day. After eight weeks of treatment, misoprostol was statistically superior to placebo in healing gastric mucosal injury (70% vs 25%) and duodenal mucosal injury (86% vs 53%). Patients with gastric or duodenal ulcers on admission had superior ulcer healing rates with misoprostol (67% vs 26%). There was no evidence of interference with the antirheumatic properties of aspirin. Mild to moderate adverse experiences were equally noted in misoprostol and placebo groups. Misoprostol, coadministered with aspirin, is well tolerated and highly effective in healing aspirin-associated gastroduodenal lesions in patients with rheumatoid arthritis without altering the therapeutic benfits of aspirin.