Low-dose aspirin (LDA) is the mainstay of prophylactic antiplatelet therapy for patients with cardiovascular and cerebrovascular diseases. LDA induces gastrointestinal mucosal injury directly and indirectly via reduced mucosal prostaglandin by inhibition of cyclooxygenase. Dual antiplatelet therapy, such as a combination of LDA and thienopyridine derivatives, is often used after implantation of a drug-eluting stent. However, dual antiplatelet therapy significantly increases the risk of gastrointestinal bleeding. Proton pump inhibitors (PPI) reduce the risk of gastroduodenal bleeding in patients receiving dual antiplatelet therapy but attenuate the antiplatelet effect of clopidogrel, the most commonly used thienopyridine derivative. The optimal prophylaxis strategy for gastrointestinal bleeding in patients receiving antiplatelet therapy remains to be determined.