SUMMARY Background Cytochrome P450 2C19 (CYP2C19) is the principle enzyme responsible for converting clopidogrel into its active metabolite and genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity/expression. Objective We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD). Patients/Methods We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and ADP-stimulated platelet aggregation pre- and post-clopidogrel exposure. Results The CYP2C19*2 and CYP2C19*17 variants were in LD (|D’|=1.0; r2=0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (beta=−5.24, P=3.0×10−9 and beta=−5.36, P=3.3×10−14, respectively) and post-treatment ADP-stimulated platelet aggregation (beta=7.55, P=2.9×10−16 and beta=7.51, P=7.0×10−15, respectively). In contrast, CYP2C19*17 was associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (beta=1.57, P=0.04 and beta=−1.98, P=0.01, respectively) but not after (beta=0.40, P=0.59 and beta=−0.13, P=0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response. Conclusions Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant.