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Prior studies have reported controversial conclusions regarding the risk of adverse cardiovascular events in patients using proton-pump inhibitors (PPIs) combined with clopidogrel therapy, causing much uncertainty in clinical practice. We sought to evaluate the safety of PPIs use among high-risk cardiovascular patients who underwent percutaneous coronary intervention (PCI) in a long-term follow-up study.A total of 7868 consecutive patients who had undergone PCI and received dual antiplatelet therapy (DAPT) at a single center from January 2013 to December 2013 were enrolled. Adenosine diphosphate (ADP)-induced platelet aggregation inhibition was measured by modified thromboelastography (mTEG) in 5042 patients. Propensity score matching (PSM) was applied to control differing baseline factors. Cox proportional hazards regression was used to evaluate the 2-year major adverse cardiovascular and cerebrovascular events (MACCEs), as well as individual events, including all-cause death, myocardial infarction, unplanned target vessel revascularization, stent thrombosis, and stroke.Among the whole cohort, 27.2% were prescribed PPIs. The ADP-induced platelet aggregation inhibition by mTEG was significantly lower in PPI users than that in non-PPI users (42.0 ± 30.9% vs. 46.4 ± 31.4%, t = 4.435, P < 0.001). Concomitant PPI use was not associated with increased MACCE through 2-year follow-up (12.7% vs. 12.5%, χ2 = 0.086, P = 0.769). Other endpoints showed no significant differences after multivariate adjustment, regardless of PSM.In this large cohort of real-world patients, the combination of PPIs with DAPT was not associated with increased risk of MACCE in patients who underwent PCI at up to 2 years of follow-up.