Objectives We analyzed the antiplatelet effects of different P2Y12 receptor blockers with VerifyNow P2Y12 assay (VN-P2Y12) and light transmittance aggregometry (LTA). Background The point-of-care VN-P2Y12 has been used to assess the antiplatelet effects in clopidogrel-treated patients but has not been evaluated in detail in patients treated with ticagrelor. Methods Patients were randomly assigned to either ticagrelor [180 mg loading/90 mg twice daily (n = 37)] or clopidogrel [600 mg loading/75 mg daily (n = 39)] on top of aspirin treatment, and platelet reactivity was measured serially during onset, maintenance, and offset phases. High on-treatment platelet reactivity (HPR) was defined as 5 and 20 μM adenosine diphosphate-induced maximal platelet aggregation ≥46% and ≥59%, respectively, and P2Y12 reaction units ≥235. Results Platelet function measured by VN-P2Y12 correlated well with LTA (.812 ≤ ρ ≤ .823, P < .001). VN-P2Y12 “BASE” values were consistent during administration of both agents. Calculated and reported percent inhibitions by VN-P2Y12 were similar (difference, −0.6%; 95% agreement limits, −22.9% to 21.6%). Platelet inhibition by VN-P2Y12 during clopidogrel and ticagrelor administrations was comparable to platelet inhibition by LTA. HPR determined by LTA and VN-P2Y12 were well matched, and the risk stratification between the two methods showed strong agreement after both therapies (κ > .7). Conclusions The VerifyNow P2Y12 assay is effective in assessing the antiplatelet effects and in identifying HPR during clopidogrel or ticagrelor therapy.