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Helicobacter pylori(H. pylori)infection and NSAID/low-dose aspirin (ASA) use are associated with peptic ulcer disease. The risk of peptic ulcer bleeding (PUB) associated with the interaction of these factors remains unclear. The objective of this study was to determine the risk of PUB associated with the interaction betweenH. pyloriinfection and current nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose ASA use.This was a case-control study of consecutive patients hospitalized because of PUB. Controls were matched by age, sex, and month of admission.H. pyloriinfection status was determined in all cases and controls by serology. Drug use was determined by structured questionnaire. Adjusted relative risk (RR) associated with different factors, and the interaction between NSAID/ASA andH. pyloriinfection was estimated by logistic regression analysis.The study included 666 cases of PUB and 666 controls; 74.3% cases and 54.8% controls (RR: 2.6; 95% confidence interval (CI): 2.0–3.3) tested positive forH. pyloriinfection; 34.5% of cases had current NSAID use compared with 13.4% of controls (RR: 4.0; 95% CI: 3.0–5.4). Respective proportions for low-dose ASA use were 15.8 and 12%, respectively (RR: 1.9; 95% CI: 1.3–2.7). The RR of PUB for concomitant NSAID use andH. pyloriinfection suggested an additive effect (RR: 8.0; 95% CI: 5.0–12.8), whereas no interaction was observed with ASA use (RR: 3.5; 95% CI: 2.0–6.1).NSAID, low-dose ASA use, andH. pyloriinfection are three independent risk factors for the development of PUB, but there were differences in the interaction effect between low-dose ASA (no interaction) or NSAID (addition) use andH. pyloriinfection, which may have implications for clinical practice in prevention strategies.