Aim: To investigate the role of Helicobacter pylori, expressing the virulence marker CAGA (cytotoxin associated gene product A) in ulcer complications and its interaction with nonsteroidal anti-inflammatory drugs (NSAIDs) and other risk factors. Design: Case control study using conditional logistic regression analysis. Setting: University and City Hospitals, Nottingham. Subjects: 203 consecutive patients with ulcer bleeding and 203 age- and sex-matched controls. Results: Ulcer bleeding was more likely with positive H. pylori serology (odds ratio = 3.3. 95%, CI: 1.7-6.6 for CagA positive, but only OR = 1.6. 95%, CI: 0.7-3.7 for CagA negative serology), current smoking (OR 2.2, 95%, CI: 1.04-4.7), aspirin less than or equal to 300 mg daily (OR 7.7, 95% CI: 2.8-20.6). all other nonsteroidal anti-inflammatory drugs (NSAIDs: OR 10.6, 951% CI: 3.1-35.7 for less than or equal to 1 defined daily dose lower and OR 22.6, 95% CI: 6.2-82.0 for higher doses) and past ulcer history (OR 5.6, 95% CI: 2.3-14.1). Aspirin less than or equal to 300 mg daily was used by 25.1% of patients vs. 7.4% of controls. Smoking only enhanced risk in the presence of H. pylori, with a synergistic interaction (interaction odds ratio = 4.9, 2.4-9.9, P = 0.002). Conversely, risks with non-aspirin NSAIDs were reduced in the presence of H. pylori. particularly if CagA-positive (interaction odds ratio = 0.21, 0.05-0.9, P = 0.03). Conclusions: CagA positive H. pylori infection is associated with an increased risk of ulcer bleeding. The risk from non-aspirin NSAIDs is even higher, but is less in H. pylori infected people. Low-dose aspirin is now commonly, associated with ulcer bleeding.