Objectives The aim of this study was to assess the impact of genetic polymorphisms on platelet inhibition by clopidogrel maintenance therapy in patients treated with percutaneous coronary intervention (PCI). Background Genetic polymorphisms, especially the CYP2C19 isoenzyme, can decrease the active metabolite of clopidogrel and have increased the risk of major adverse cardiovascular events. Although prevalence of the CYP2C19 polymorphism is much higher in East Asian than Caucasian (about 60% vs. 30%), the risk of long-term adverse ischemic events seems not different. Therefore, the impact of genetic polymorphisms must be evaluated in patients on long-term maintenance therapy of clopidogrel. Methods We consecutively enrolled PCI-treated 200 patients on chronic standard dual antiplatelet therapy (clopidogrel 75-mg/day ��� 6 month). Platelet reactivity was assessed with conventional aggregometry and the VerifyNow P2Y12 assay. CYP3A5, CYP2C19 and ABCB1 genotyping was performed for all patients. High on-clopidogrel platelet reactivity (HPR) was defined as the highest quartile of maximal PR after 5 關mol/l ADP stimuli (��� 56%). Results Although reduced metabolizers of CYP3A5*3 and ABCB1 genotypes did not show increased PR, PR showed an increased trend proportionally according to the number of the CYP2C19 variant allele(s). Patients with HPR were more frequently female (44.0% vs. 28.0%, p = 0.036) and on calcium channel blocker (CCB) (48.0% vs. 31.3%, p = 0.033), and smoked less (8.0% vs. 20.7%, p = 0.041), compared to those with normal response to clopidogrel. When we classified CCBs into P-glycoprotein (Pgp) inhibiting (n = 23) and non-Pgp-inhibiting CCBs (amlodipine, n = 48), there were significant differences in PRs between patients without CCB vs. on Pgp-inhibiting CCB vs. on non-Pgp-inhibiting CCB (5 關mol/l ADP-induced maximal PR: 40.6짹16.8% vs. 46.0짹14.1% vs. 50.0 짹 17.1%, p = 0.003). In multivariate analysis, use of amlodipine was the only independent predictor of HPR (odds ratio; 3.717, 95% confidence interval; 1.155 to 6.211, p = 0.022). Conclusions Among PCI-treated patients on long-term maintenance therapy of clopidogrel, genetic polymorphisms do not increase the risk of HPR, whereas amlodipine use can significantly predict the risk of HPR.