Drug-eluting stent (DES) thrombosis has a multifactorial etiology. Variable responsiveness to antiplatelet therapy likely contributes to its pathogenesis. We aimed to determine whether patients who had experienced DES thrombosis compared with a cohort of patients who had not would exhibit greater platelet reactivity and a greater prevalence of aspirin and clopidogrel resistance. The effect of aspirin and clopidogrel on platelet reactivity was determined after angiographically proven DES thrombosis in 26 patients and in 21 patients who had not experienced stent thrombosis (ST) > or =18 months after DES implantation. Aspirin effect was assessed using the VerifyNow Aspirin Assay, and the effect of clopidogrel was assessed using the VerifyNow P2Y12 Assay and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P). Aspirin resistance was present in 23% of patients with ST and 5% of controls (p = NS). Clopidogrel resistance was present in 40% of patients with ST and 14% of controls using the P2Y12 assay (p = 0.02) and 90% of patients with ST and 67% of controls using the VASP-P assay (p = NS). Mean aspirin reaction units were significantly greater among all patients with ST and those with early ST compared with controls (477 +/- 89 vs 429 +/- 58, p = 0.04; and 485 +/- 84 vs 429 +/- 58, p = 0.02, respectively). Mean P2Y12 reaction units were significantly greater among patients with early ST compared with controls (265 +/- 102 vs 184 +/- 76, p = 0.01). The results of the VASP-P assay did not correlate with the presence of ST. In conclusion, patients who experienced DES thrombosis demonstrated significantly greater rates of clopidogrel resistance as determined by P2Y12 reaction units, but not VASP-P, compared with patients without DES thrombosis. Aspirin reaction units were significantly greater in the DES thrombosis population. Point-of-care testing with the VerifyNow Aspirin and P2Y12 Assays has the potential to identify patients at increased risk of ST, particularly early ST, after DES deployment.