This study was undertaken to evaluate the efficacy of misoprostol taken twice daily for the healing of duodenal ulcer. Three hundred thirty patients with endoscopically proven duodenal ulcer participated in a multicenter, double-blind, controlled trial comparing placebo with misoprostol 200 micrograms and 400 micrograms twice daily for up to four weeks. Patient characteristics were similar in all three treatment groups. Ulcers were between 0.3 cm and 2.0 cm in length. Healing was determined by endoscopy at two weeks; if ulcers were not healed, endoscopy was repeated at four weeks. All patients were given Al(OH)3 antacid (up to 54 meq a day) to be used as needed for pain. Healing rates at four weeks for a total of 280 evaluable patients in the three treatment groups were as follows: misoprostol 400 micrograms bid, 65.4%; misoprostol 200 micrograms bid, 52.9%; and placebo, 42.2%. Misoprostol 400 micrograms bid was superior to placebo (P = 0.002) in healing ulcers. However, the healing rate for misoprostol 200 micrograms bid did not differ significantly from placebo. The percentage of nonsmokers who healed at four weeks was higher than that of smokers in both misoprostol-treatment groups, although the difference was not analyzed for statistical significance. There were no differences in antacid consumption or pain relief among the three experimental groups during the study. Diarrhea was the most common side effect but was mild and self-limiting, occurring in 8.9%, 5.9%, and 1.8% of the misoprostol 400 micrograms, 200 micrograms, and placebo groups, respectively. These results indicate that misoprostol 400 micrograms taken twice daily for four weeks is effective and safe for the treatment of duodenal ulcers.