The effect of nonsteroidal antiinflammatory drugs (NSAIDs) on duodenal mucosa was assessed both retrospectively and prospectively. In 444 patients with duodenal ulcer, the incidence of upper gastrointestinal bleeding was five times higher in 56 patients who were treated with NSAIDs than in those who did not receive NSAIDs. Indomethacin and naproxen had the most potent damaging effects. In a control group of patients with gastric ulcer, nine out of 134 had taken NSAIDs. The incidence of bleeding in these patients was three times higher than in those who were not on NSAIDs. The effect of indomethacin, 150 mg/day, on the upper gastrointestinal tract was examined in a prospective study of 75 patients with acute musculoskeletal disorders. Endoscopy after 1 week of therapy showed that 45% had mucosal damage in the duodenum, and this was as frequent and as severe as the gastric mucosal damage. In most instances, the duodenal damage was erosive duodenitis.