BACKGROUND: -A recent report suggested that carriers of the Q allele of the PON1 Q192R polymorphism had decreased biotransformation of clopidogrel into its active metabolite and decreased efficacy of clopidogrel in preventing cardiovascular events. Furthermore, PON1 has been reported to have a central role in the antioxidant function of HDL and the Q192R polymorphism has been previously associated with cardiovascular risk in patients not treated with clopidogrel. METHODS AND RESULTS: -5,059 patients from the CURE randomized trial that demonstrated benefits of clopidogrel versus placebo in preventing cardiovascular events in acute coronary syndromes were genotyped for the PON1 Q192R polymorphism. Clopidogrel compared to placebo significantly reduced the first primary efficacy outcome, irrespective of PON1 Q192R genotype (P=0.07 for heterogeneity). No association was observed between the Q192R polymorphism and cardiovascular events in the overall sample (HR= 1.09 per allele; 95%CI 0.95-1.24; p=0.23). However, an association was observed between the Q allele and increased cardiovascular events in the placebo group (HR=1.23 per allele; 95%CI 1.03-1.47; p=0.03), but not in the clopidogrel group (HR=0.93 per allele; 95%CI 0.76-1.13; p=0.46). In 1,156 atrial fibrillation patients from the ACTIVE trial, there was no evidence of interaction between PON1 genotype and clopidogrel for any outcome or for an association between genotype and cardiovascular events. CONCLUSIONS: -In conclusion, our study shows that PON1 Q192R genotype does not modify the efficacy and safety of clopidogrel in ACS patients. Further studies are needed to confirm or refute the association of the Q allele with adverse cardiovascular events independently of clopidogrel in secondary prevention patients.