Objective: To investigate the significance of CYP2C19 gene polymorphism determination in optimizing antiplatelet therapy for patients with arteriosclerosis obliterans (ASO) of the lower extremities. Methods: Eighty ASO patients scheduled for lower extremity bypass surgery or procedures of interventional balloon dilation plus stent placement were enrolled and randomly designated to either study group or control group, and genotyping for the polymorphic alleles of CYP2C19*2 and CYP2C19*3 was performed in all patients. Patients in control group were treated with aspirin plus clopidogrel regimen, while in study group, patients with extensive metabolizer phenotypes received aspirin plus clopidogrel regimen and those with poor metabolizer phenotypes were given aspirin plus clopidogrel and sarpogrelate regimen according to the results of genotyping. The occurrence of clopidrogrel resistance in the two groups of patients was observed and compared. Results: The incidence of clopidrogrel resistance in the entire group was 38.75% (31/80), and the occurrence of clopidrogrel resistance showed no association with age, sex, or concomitant diseases of the patients, or with other drug administration (all P>0.05). The incidence of clopidrogrel resistance in extensive metabolizers was 33.33% in study group and 37.93% in control group respectively, which showed no statistical difference (P=0.469); whereas, the incidence of clopidrogrel resistance in poor metabolizers was 23.07% in study group and 72.73% in control group respectively, where the difference reached statistical significance (P=0.017). Conclusion: Among patients with lower-extremity ASO requiring long-term clopidogrel therapy, sarpogrelate addition can effectively reduce the incidence of clopidogrel resistance for those with poor metabolizer phenotypes classified by CYP2C19 genotyping assay.