Antithrombotic drugs have been increasingly used for treating ischemic cardiovascular diseases among the elderly in Japan. However, antithrombotic drugs are known to be risk factors for gastrointestinal injury. Therefore, we conducted a pharmacoepidemiologic study on patients receiving antithrombotic drugs to identify the risk factors for gastrointestinal injury. This retrospective case-control study included patients who were prescribed antithrombotic drugs at the Ehime University Hospital between April and September 2010. Of the 3271 patients who received antithrombotic drug therapy, 172 (5.3%) developed gastrointestinal injuries, including gastric ulcers, duodenal ulcers, and hemorrhagic gastrointestinal injuries. Further, the incidence of gastrointestinal injury was higher in patients with hypertension than in those without (p<0.0001). Multivariate adjusted odds ratios and 95% confidence intervals were calculated using stepwise logistic regression. The adjusted odds ratios for gastrointestinal injury were 1.56 (95% confidence interval 1.07-2.36) for hypertension, 1.70 (1.17-2.50) for low-dose aspirin, 2.77 (1.70-4.49) for clopidogrel, 1.95 (1.23-3.08) for warfarin, and 4.13 (2.88-5.95) for nonsteroidal anti-inflammatory drugs. On the other hand, the non-adjusted odds ratio for drug-associated gastrointestinal injury was 0.43 (0.20-0.84) for eicosapentaenoic acid (EPA). In addition, we found that patients aged 70 years or older were at increased risk of drug-associated gastrointestinal injury. These findings suggest that while many antithrombotic drugs are risk factors for gastrointestinal injury, EPA may be a safe option for suppressing or preventing gastrointestinal injury.