Background Dual anti-platelet treatment with aspirin and clopidogrel is established foundation for patients undergoing percutaneous coronary intervention (PCI) to prevent thrombotic events. The present study was conducted to examine whether the CYP2C19 681G＞A polymorphism and cigarette smoking had independent or interactive effect on response to clopidogrel.Methods Among 722 Chinese Han patients undergoing elective coronary stent placement due to stable angina pectoris,a loading dose of 300 mg clopidogrel was given to all patients and a daily maintenance dose of 75 mg for a minimum of 12 months. CYP2C19 681G＞A polymorphism was genotyped. The platelet reactivity was measured by light transmittance aggregometry (LTA) with 5 μmol/L adenosine diphosphate (ADP) induced. The poor response was defined as 10% or less absolute difference between aggregation at baseline and 24 hours after loading dose of clopidogrel.Results The results showed that the poor-response to clopidogrel was presented in 105 patients (14.5%). Overall, the genotype GA/AA carriers were likely to be poor-responsive cases (19.6% vs. 11.0%, P=0.001) with odds ratio (OR) of 1.971 (95% CI: 1.296-2.998, P=0.002), compared with the GG homozygotes. Meanwhile, compared with nonsmokers,the smokers showed lower rate of poor-response (10.9% vs. 17.3%, P=0.015) with OR of 0.582 (95% CI: 0.374-0.904,P=0.016). The smokers with GG genotype had the lowest risk with OR of 0.487 (95% CI: 0.246-0.961, P=0.038) while nonsmokers with GA/AA genotype had the highest risk of poor-response with OR of 1.823 (95% CI: 1.083-3.068,P=0.024), compared with nonsmokers with GG genotype. However, there was no significant interaction between genotype and smoking.Conclusion Our study indicated that both CYP2C19 polymorphism and smoking independently affected response to clopidogrel.