Objectives The aim of this study was to evaluate the effects of CYP2C19 and paraoxonase-1 (PON1) genotypes on clinical outcome of clopidogrel in patients with stable angina or acute myocardial infarction (AMI), respectively. Background Limited data exist on the impact of CYP2C19 or PON1 polymorphisms and their interaction on clinical outcome of clopidogrel therapy in patients with stable angina or AMI, especially in Asian population with higher frequencies of CYP2C19 poor metabolizer (PM) and PON1 QQ192 genotypes. Methods We enrolled 2188 patients (AMI: 532 and angina: 1656) undergoing PCI and clopidogrel therapy for at least 1 year. The functional variants of 8 genes modulating clopidogrel response (ABCB1, CYP2C19, PON1, etc) were evaluated for the risk of cardiovascular events. The primary outcome was a composite of death from any cause, nonfatal MI or stroke during 1 year of follow-up. Results Only CYP2C19 genotype has a significant effect on P2Y12 reactivity unit, but both CYP2C19 poor metabolizer (PM) and PON1 QQ192 genotype were associated with higher risk of primary outcome in AMI patients (p=0.011 and p=0.035), but not in angina patients. The risk of adverse events was highest when both genotypes of CYP2C19 PM and PON1 QQ192 were combined in AMI subpopulation (adjusted hazard ratio [95% confidence interval), 10.16 [2.84-36.40[, p<0.001). Conclusion Both CYP2C19 and PON1 genotypes are predictive genetic biomarkers for clinical outcome of clopidogrel therapy in patients with AMI, but not with angina.