Objective— Observational studies have reported enhanced response to clopidogrel in smokers (the smokers' paradox). We examined whether genetic variations in the cytochrome and drug transporter system are associated with the effect of smoking on clopidogrel response. Methods and Results— Clopidogrel on-treatment platelet reactivity (OPR) was measured in 1431 consecutive patients who underwent coronary angiography. Gene samples were available and genotyping was successful in 1123 patients. Nine candidate single-nucleotide polymorphisms in 5 cytochrome genes and 1 drug transporter gene were assessed. The mean OPR of the entire population was 241.9±79.3 (P2Y 12 reaction units). Two hundred forty-nine (17%) smokers had lower OPR compared with 1182 (83%) nonsmokers (227.6±76.0 versus 244.9±79.7, P =0.001). Among the 9 single-nucleotide polymorphisms, only CYP1A2 showed a genotype-dependent change in the effect of smoking on OPR. After adjustment for possible confounding factors, cigarette smoking was associated with a lower OPR by −19 P2Y 12 reaction units ( P =0.009) and lower risk for high OPR (odds ratio [OR], 0.48; 95% CI, 0.31 to 0.74) in the AA and CA genotypes but not in the CC genotype. Conclusion— Enhanced clopidogrel response in smokers, known as the smokers' paradox, is not universal but was observed only in cytochrome P450 CYP1A2 (−163C>A) A-allele carriers, suggesting a genotype-dependent effect of smoking on clopidogrel responsiveness.