Background: The risk of major upper gastrointestinal bleeding associated with various antiplatelet drugs and the protection conferred by gastroprotective agents are not well defined. Aim: To estimate the risk of upper gastrointestinal bleeding associated with the use of antiplatelet drugs and its prevention by gastroprotective agents. Methods: In a case-control study, we compared all cases of upper gastrointestinal bleeding from a gastric or duodenal lesion in patients over 18 years of age (2813 cases), with 7193 matched controls. Odds ratios of upper gastrointestinal bleeding for individual antiplatelet drugs with adjustment for potential confounders were estimated. Results: The individual risks of upper gastrointestinal bleeding were cardiovascular acetylsalicylic acid 4.0 (3.2-4.9), clopidogrel 2.3 (0.9-6.0), dipyridamole 0.9 (0.4-2.0), indobufen 3.8 (1.2-12.2), ticlopidine 3.1 (1.8-5.1) and triflusal 1.6 (0.9-2.7). Concomitant proton pump inhibitors decreased all risk estimates. For acetylsalicylic acid plus a proton pump inhibitor, the odds ratio was 1.1 (0.5-2.6). As a group, antiplatelet drugs accounted for 14.5% of all cases of upper gastrointestinal bleeding, i.e. 58 per million per year (334 per million per year among those older than 70 years). Conclusions: The risk of upper gastrointestinal bleeding is substantially decreased by the concomitant use of proton pump inhibitors. The risk of acetylsalicylic acid plus a proton pump inhibitor seems lower than that of ticlopidine or clopidogrel. © 2006 Blackwell Publishing Ltd.