The aim of this study is to investigate the effect of CYP2C19 polymorphism and cotherapy with rabeprazole or esomeprazole on the antiplatelet effect of clopidogrel. Patients receiving clopidogrel 75 mg ± rabeprazole or esomeprazole underwent genotyping for CYP2C19*2 and CYP2C19*3, and vasodilator-stimulated phosphoprotein testing to measure platelet reactivity index (PRI). Two hundred thirty-nine consecutive patients were enrolled as follows: 92 clopidogrel (C group), 94 clopidogrel + rabeprazole (CR), and 53 clopidogrel + esomeprazole (CE). Forty-five patients had loss of function (LOF) polymorphism (43 heterozygous; 2 homozygous mutant for CYP2C19*2). The mean PRI was 20.7% ± 21.9% in the C group, 19.1% ± 20.9% in the CR group, and 24.5% ± 22.9% in the CE group (P = NS). High on-treatment platelet reactivity (HPR), defined as PRI >50%, was observed in 12 (13.0%), 13 (13.8%), and 10 (18.9%) patients on C, CR, and CE, respectively (P = NS). HPR was similar in rapid metabolizers between groups. On multivariate logistic regression, neither CYP2C19 LOF alleles nor proton pump inhibitor cotherapy were associated with HPR. The use of proton pump inhibitors was indicated in 30.6% of recipients. As a conclusion, CYP2C19*2 LOF allele and the use of esomeprazole or rabeprazole have no effect on the action of clopidogrel.