Long-term (at least one year) dual anti-platelet therapy incorporating aspirin and clopidogrel is currently recommended following percutaneous coronary intervention with placement of a drug-eluting stent (DES). Genetic variants in both the ABCB1 and CYP2C19 genes have been associated with cardiovascular events among patients on clopidogrel. We examined the concurrent contribution of the CYP2C19 *2 and *17 alleles and the ABCB1 3435 alleles to one-year clinical risk among patients (n=1,034 on clopidogrel therapy following the placement of a DES. For CYP2C19*2, event rates were 8.4%, 10.9% and 44.4% for patients with 0, 1 and 2 *2 alleles, respectively (p=0.016). ABCB1 3435 was not associated with events in univariate analysis. However, 72% of patients with a *2 variant also possessed the ABCB1 3435 C allele; among these patients (*2/C genotype) the event rate for myocardial infarction (MI) was 14.2% vs. 6.9% for those lacking both *2 and C alleles (p=0.027) and for MI/death, 16.9% vs. 9.6% (p=0.046). Overall for all genotypes, the presence of the gain-of-function (protective) *17 allele significantly reduced the one-year rate of MI from 11.1% to 7.0% (p=0.045) and trended to reduce the combined rate of MI/death from 13.8% to 10.5% (p=0.182). In conclusion, the ABCB1 3435 locus and the *2 allele combine to impart a significant trend toward increased risk. This trend was largely reversed by the simultaneous carriage of one or two *17 alleles. These findings suggest that assessment of a combined genotype may improve risk assessment.