The association between nonsteroidal antiinflammatory drugs (NSAIDs) and upper gastrointestinal complications is well documented. However, epidemiologic data on the risk of clinically symptomatic but uncomplicated peptic ulcer are quite limited. The authors studied the association between prescription NSAIDs and the risk of symptomatic ulcer in a population-based cohort of 458,840 persons and 1,167,469 person-years in the United Kingdom between 1995 and 1999 and conducted a nested case-control analysis of 1,197 cases and 10,000 controls. The relative risk and 95% confidence intervals were estimated and adjusted for several factors known to be associated with gastrointestinal damage. The incidence rate of symptomatic ulcer was 1.03 (95% confidence interval (CI): 0.97, 1.08) cases per 1,000 person-years. Compared with nonusers, the relative risk was 2.9 (95% CI: 2.3, 3.6) for aspirin and 4.0 (95% CI: 3.2, 5.1) for nonaspirin NSAID users. For aspirin users, the relative risk was similar for doses up to 300 mg daily and for both gastric and duodenal ulcers. For nonaspirin NSAIDs, the relative risk was 2.6 (95% CI: 2.0, 3.5) for medium daily doses or lower and 4.9 (95% CI: 3.8, 6.5) for high daily doses; it was 5.6 (95% CI: 3.9, 8.2) for gastric and 3.1 (95% CI: 2.3, 4.2) for duodenal ulcers. The risk of symptomatic ulcer for aspirin and nonaspirin NSAIDs was elevated throughout treatment. These findings suggest that NSAIDs might not only complicate but also originate clinically relevant peptic ulcers.