Background <p>Proton pump inhibitors (PPIs) are widely used in combination with dual antiplatelet therapy (DAPT) to reduce the risk of gastrointestinal bleeding; however, some PPIs may interfere with clopidogrel metabolism through CYP2C19 inhibition. Potassium-competitive acid blockers (P-CABs) have emerged as alternatives to PPIs, although their effectiveness in patients receiving DAPT have not been sufficiently explored.</p> Aim <p>This study aimed to compare the effectiveness of PPIs and P-CABs in preventing cardiovascular events and gastrointestinal bleeding among patients receiving DAPT after coronary stent implantation.</p> Method <p>A retrospective cohort design was employed using nationwide claim data from South Korea. The study included patients who received aspirin-clopidogrel DAPT with PPI or P-CAB for a minimum of 60 days. After applying propensity score matching (PSM) at a 1:1 ratio, survival analysis was conducted. The primary outcome was a composite of acute myocardial infarction, ischemic stroke, revascularization, and in-hospital mortality. Secondary outcomes involved the individual components of the composite outcome and gastrointestinal bleeding.</p> Results <p>The initial cohort included 39,234 patients in the PPI group and 3,434 in the P-CAB group. After 1:1 PSM, 3,434 patients were included in each group. No statistically significant differences were observed between the PPI and P-CAB groups for the primary outcome (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.68–1.07; <i>p</i> = 0.167) and gastrointestinal bleeding (HR, 1.36; 95% CI, 0.76–2.42; <i>p</i> = 0.3).</p> Conclusion <p>Both PPIs and P-CABs appear to be viable options for acid suppression in patients undergoing DAPT, with no significant differences in cardiovascular or gastrointestinal outcomes.</p>