BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (LDA), non-aspirin antiplatelet medications (APs), and anticoagulant medications (ACs) increase the risk of gastrointestinal bleeding. AIM: To examine whether NSAIDs, LDA, APs, and ACs use is associated with bleeding from gastroduodenal ulcers. METHODS: This was a case-control study of patients with endoscopically verified gastroduodenal ulcer diagnosed at our institution from 2004 to 2011. Among 1,611 patients, we identified those who required endoscopic hemostasis for bleeding ulcers as cases. Age-matched, sex-matched, and Helicobacter pylori status-matched patients who did not require therapeutic interventions served as controls. Use of NSAIDs, LDA, APs, and ACs within 2 weeks prior to the endoscopy was compared between cases and controls, and effects on ulcer bleeding were calculated. RESULTS: We recruited 341 cases and 668 controls. The site and number of ulcers were not different between groups. Multivariate analyses revealed that LDA and NSAIDs, individually, were associated with the increase in the risk of bleeding (OR 1.80 and 95 % CI 1.18-2.75 for LDA; 1.35 and 1.01-1.80 for NSAIDs). In addition, a combination of LDA and NSAIDs or LDA and APs contributed more profoundly to the bleeding (OR 3.59 and 95 % CI 1.19-10.81 for LDA/NSAIDs; OR 6.70 and 95 % CI 1.83-24.50 for LDA/APs). However, ACs, alone or in combination, were not associated with bleeding ulcers. CONCLUSIONS: Both LDA and NSAIDs are risk factors for upper GI bleeding in patients with gastroduodenal ulcer, while ACs are unrelated to the increased risk. The risk of bleeding with LDA may increase with simultaneous use of APs.