OBJECTIVES: The objective of the study was to determine the prevalence of high on-treatment platelet reactivity (HPR) in coronary artery disease patients enrolled in the ONSET/OFFSET and RESPOND studies. BACKGROUND: HPR has been linked to the occurrence of adverse events after stenting in patients treated with clopidogrel (C) and aspirin. Prevalence of HPR after treatment with ticagrelor (T), a reversible oral P2Y(12) receptor antagonist developed to overcome the limitations of C, is unknown. METHODS: Patients were treated with T (n = 106) or C (n = 103) on top of aspirin therapy. HPR was defined by published cutoff points associated with post-percutaneous coronary intervention ischemic risk: >59% 20 μM adenosine diphosphate-induced aggregation (light transmittance aggregometry), >235 P2Y12 reaction unit by VerifyNow P2Y(12) assay (VerifyNow, San Diego, CA), and >50% platelet reactivity index by vasodilator-stimulated phosphoprotein phosphorylation assay (VASP-P). Proportion differences for T versus C were analyzed by χ(2) test for each time point. Correlations (R) were analyzed by the Pearson method. RESULTS: Ticagrelor was associated with a significantly lower prevalence of HPR (0%-8%) compared with C (21%-81%) at 2, 4, 8, and 24 hours and ≥2 weeks postdosing (P < .0001, for all assays). The R values between light transmittance aggregometry and VerifyNow/VASP-P were all ≥0.43, P < .0001. CONCLUSIONS: The above data represent the largest serial pharmacodynamic evaluation of the comparative effects of T versus C. Ticagrelor was rapidly and consistently associated with a very low prevalence of HPR compared with C, as determined by multiple established methods to measure platelet reactivity. These results provide a mechanism for the lower ischemic event rate associated with T therapy reported in the PLATO trial.