Vascular endothelial growth factor receptor 2 (VEGFR-2) plays a central role in atherogenesis. We investigated the correlation between VEGFR-2 polymorphisms and the risk of clopidogrel resistance (CR) in patients with coronary heart disease (CHD). The study involved 275 patients with CHD undergoing percutaneous coronary intervention and on antiplatelet clopidogrel therapy. The participants were divided into CR group (n = 59) and non-CR group (NCR, n = 216) based on maximum platelet aggregation measurements. VEGFR-2 gene polymorphisms, +1192C>T (rs2305948), +1416T>A (rs1870377), and -271A>G (rs7667298), were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Enzyme-linked immunosorbent assay was used to measure serum transforming growth factor, beta receptor 2 levels. CR was found in 59 patients (20.45%). A significantly higher proportion of patients in the CR group had a history of diabetes mellitus compared with the NCR group (P < 0.05). Genotype and allele frequency of VEGFR-2 +1192C>T (rs2305948) was significantly higher in the CR group than in the NCR group (all P < 0.01). In the VEGFR-2 +1192C>T (rs2305948), the angina pectoris, recurrent myocardial infarction, and combined end point events were significantly more prevalent in the TT carriers than in the CC + CT carriers. In VEGFR-2 -271A>G (rs7667298), the GG carriers had a lower proportion of target lesion revascularization and angina pectoris in contrast to the AA + AG carriers (all P < 0.05). Based on our results, VEGFR-2 +1192C>T (rs2305948) polymorphism is strongly associated with increased CR and main adverse cardiovascular event incidence in patients with CHD undergoing percutaneous coronary intervention. Additionally, patients with CHD with diabetes mellitus history were more likely to develop CR. The associations of +1416T>A (rs1870377) and -271A>G (rs7667298) polymorphisms with CR were inconclusive and will need to be examined further.