BACKGROUND: A discrepancy exists between the European and American guideline recommendations for the routine use of proton pump inhibitors (PPIs) in patients treated with dual antiplatelet therapy (DAPT). AIMS: This study aimed to determine the association between the co-prescription of PPIs and DAPT and the occurrence of gastrointestinal bleeding and ischaemic events in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). METHODS: A search was conducted using a nationwide Korean claims database to identify patients with AMI undergoing PCI with DAPT. Patients were matched using a large-scale propensity score (PS) algorithm according to the co-prescription of PPIs. The primary efficacy endpoint was major gastrointestinal bleeding requiring transfusion with hospitalisation within 1 year. The primary safety endpoint was major adverse cardiac and cerebrovascular events (MACCE), a composite of cardiovascular death, spontaneous myocardial infarction, repeat revascularisation and ischaemic stroke within 1 year. RESULTS: Among the total population, 30.0% of patients (n=35,566) received PPIs with DAPT after PCI for AMI. After PS matching, 35,560 pairs were generated. Compared to patients without PPIs, those on PPIs were associated with a significantly lower 1-year risk of major gastrointestinal bleeding (0.7% vs 0.4%, hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.48-0.73). The 1-year risk of MACCE did not differ significantly between the groups with or without PPIs (13.4% vs 13.1%, HR 0.98, 95% CI: 0.94-1.02). The beneficial effects of PPIs on gastrointestinal bleeding, without increased risk of cardiovascular events, were observed consistently, regardless of P2Y CONCLUSIONS: In real-world data from a large study of East Asian patients with AMI undergoing PCI and maintaining DAPT, PPI use significantly reduced the risk of major gastrointestinal bleeding without increasing ischaemic events, irrespective of bleeding risk or type of P2Y