A multicenter, double-blind, placebo-controlled trial was undertaken to evaluate the efficacy of the synthetic prostaglandin E1 analog misoprostol in preventing and healing gastric ulcer induced by nonsteroidal antiinflammatory drugs (NSAID) in patients receiving chronic NSAID therapy for osteoarthritis (OA). A total of 420 patients with OA and NSAID-associated abdominal pain who were receiving ibuprofen, piroxicam or naproxen were enrolled in the study. Endoscopy was performed at study entry and after 1, 2 and 3 months of continuous therapy with misoprostol 100 micrograms, misoprostol 200 micrograms or placebo given q.i.d. while NSAID therapy was continued. Treatment failure was defined as development of gastric ulcer (greater than 0.3 cm in diameter). The occurrence of ulcer in each misoprostol group (5.6% and 1.4% for 100 micrograms and 200 micrograms, respectively) was significantly lower (p less than 0.001) than that in the placebo group (21.7%). The statistically significant difference persisted when comparisons were restricted to development of ulcer greater than 0.5 cm in diameter (12.3, 4.2 and 0.7% for placebo, misoprostol 100 micrograms q.i.d. and misoprostol 200 micrograms q.i.d., respectively). Mild-to-moderate, self-limiting diarrhea was the most frequently reported adverse event attributed to misoprostol use.