Antiplatelet agents are commonly used in combination with proton-pump inhibitors (PPIs) in patients with acute coronary syndrome who are at risk of gastrointestinal hemorrhage. However, studies have reported that PPIs can alter the pharmacokinetics of antiplatelet agents and result in adverse cardiovascular events. We enrolled 311 patients who received antiplatelet therapy with PPIs for >30 days and 1244 matched controls following a 1:4 propensity score matching during the index period. Patients were followed up until death, myocardial infarction, coronary revascularization, or the end of the follow-up period. Patients who used antiplatelet therapy with PPIs were found to be at higher risk of mortality than the controls (adjusted hazard ratio (HR): 1.77; 95% confidence interval (CI): 1.30–2.40). The adjusted HR for patients who used antiplatelet agents with PPIs developing myocardial infarction and coronary revascularization events was 3.52 (95% CI: 1.34–9.22) and 4.74 (95% CI: 2.03–11.05), respectively. Additionally, middle-aged patients or those within 3 years of concomitant use showed a higher risk of myocardial infarction and coronary revascularization. Our findings suggest that antiplatelet therapy combined with PPIs has a higher mortality risk in patients with gastrointestinal bleeding and is associated with an increased risk of myocardial infarction and coronary revascularization.