Clopidogrel, an anti-platelet drug, is converted to its active metabolite by cytochrome P450 (CYP) enzymes such as CYP2C19. Clopidogrel users with decreased CYP2C19 function, especially CYP2C19 poor metabolizers, have been reported to exhibit less inhibition of platelet aggregation and increased cardiovascular (CV) events. As metabolism of proton pump inhibitors (PPIs) involves CYP2C19, a hypothesis that competition by PPIs may interfere with clopidogrel-induced anti-platelet action is raised. Although a retrospective cohort study suggested that clopidogrel users prescribed PPIs had increased risks of CV events, a prospective randomized trial of omeprazole vs. placebo showed no difference in CV events. Therefore, the current evidence does not justify the conclusion that PPIs decrease the clinical efficacy of clopidogrel, and further study is required to clarify this discrepancy. Combination therapy of clopidogrel and aspirin causes the development of gastric mucosal injury and gastrointestinal bleeding, which is sometimes lethal. Therefore, current consensus recommendations state that patients prescribed clopidogrel plus aspirin should receive a PPI to reduce gastrointestinal mucosal injury and bleeding. Physicians should consider the possibility of increased CV risk and gastrointestinal bleeding by concomitant clopidogrel plus aspirin treatment, and select the appropriate treatment for patients with cardiovascular diseases upon considering the benefit and risk.