Patients with endoscopically documented duodenal ulcer participated in a double-blind, multicenter trial comparing placebo with misoprostol 100 micrograms administered q.i.d. for up to four weeks in the treatment of duodenal ulcer. Ulcers were examined endoscopically at two weeks and, if not healed, again at four weeks. Acetaminophen was permitted for pain relief. At four weeks, of 286 patients admitted to the study, the cumulative healing rate for the 227 evaluable patients was 64.9% for misoprostol and 47.4% for placebo (P = 0.008). Misoprostol was also significantly superior to placebo in promoting ulcer healing when all patients entering the study (intent-to-treat cohort) were compared (P = 0.018), and in a modified intent-to-treat cohort consisting of all patients whose final endoscopic results were known (P = 0.005). Ulcer symptoms were similar in both treatment groups, and most patients in both groups were pain free at the end of the first two weeks of treatment. Diarrhea was the most frequently reported adverse experience (8.5% for misoprostol and 3.5% for placebo). This symptom was mild and self-limiting in spite of continued use of misoprostol. We conclude that misoprostol 100 micrograms q.i.d. for four weeks is safe and effective in the healing of duodenal ulcers.