Objective We sought to determine the association between the single nucleotide polymorphism of cytochrome P450 2C19(CYP2C19) 681G>A and the occurrence of clopidogrel resistance (CR) in Chinese elderly patients. Methods Totally 614 hospitalized patients (aged over 60 years) in Shenyang General Hospital between June 2010 and April 2011 were enrolled. These patients underwent successful percutaneous coronary intervention with drug-eluting stents and received treatment with dual antiplatelet regimen (aspirin plus clopidogrel). All enrolled patients were given a loading dose of 600mg clopidogrel and 300mg aspirin. Twenty-four hours later, blood samples were collected ant 20μmol/L ADP-induced platelet aggregation ratio (PAR) was assessed. The maximum residual platelet aggregation (RPA) ≥70% was defined as CR, and the RPA<70% as non-CR (NCR). Genomic DNA was extracted from whole blood samples according to standard protocols, the single nucleotide polymorphism of the CYP2C19 681G>A was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in all cases. Results CR was found in 126 cases (20.5%). CYP2C19 681G>A polymorphism was observed in this population group. The frequencies of the three kinds of genotypes (GG，GA，AA) in CR group and NCR group were 32.6%, 47.6%, 19.8% and 47.9%, 45.0%, 7.0%, respectively. The frequency of AA genotype was significantly higher in NCR group than in CR group (OR=3.03, 95% CI：1.889-5.784, P=0.003). The A allele carriers were more likely to develop CR compared with that of G allele carriers (OR=1.85, 95% CI：1.392-2.459, P=0.002). Conclusion CYP2C19 681G/A polymorphism is associated with the risk of CR, and the A allele carriers may be a possible genetic susceptibility factor for elderly patients with CR.