Background and purpose: Percutaneous coronary intervention (PCI) has been commonly used in the treatment of ischemic cardiovascular diseases, but the postprocedural in-stent restenosis (ISR) associated with altered endothelial functions has limited the clinical application of it; preventive medication with aspirin and statins has underlying adverse effects despite lowered risk of ISR. The purpose of this study was to investigate the role of angiotensin type 1 receptor (AT1R) A1166C gene polymorphisms in the development of endothelial dysfunction and ISR after PCI. Methods: A total of 483 ST-segment elevation myocardial infarction (STEMI) patients undergoing PCI were prospectively genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. The demographic, clinical, laboratory and angiographic parameters were recorded peri-procedurally and the patients were followed within 3 years. The flow-mediated dilation (FMD) was used to reflect the short-term changes in endothelial functions among different genotypes. The significance of AT1R gene polymorphisms in the development of ISR was analyzed using univariable and multivariable models. Results: Amongst 483 patients, the distribution of the AT1R genotypes (AA, AC and CC) was associated with the levels of blood biomarkers of oxidative stress and deteriorated FMD after PCI (P<0.05). In univariable and multivariable logistic regression analysis, it was shown that AT1R CC genotype is strongly associated with the development of restenosis within 3 years after PCI (OR=3.736; P<0.001; calibrated OR=4.104; P<0.001). Conclusion: The CC AT1R genotype was associated with deteriorated endothelial functions in the target vessels of PCI and intermediate to long-term ISR. Our findings contribute to the foundation of genome-based prevention for high risk groups of cardiovascular diseases and pretreatment for the patients undergoing PCI.