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Patients may respond to antiplatelet medication in 2 ways: resistance leading to higher incidence of ischemic events and hyper-response resulting in bleeds. Here, 47 patients treated with clopidogrel were tested for P2Y12 receptor-mediated platelet inhibition. Clopidogrel hyper-response was more common in patients with major (n=10) than in those with minor bleeds. Of 7 patients defined as hyper-responders, 43% had major bleeding complications. Thus, hyper-response to clopidogrel is associated with increased risk of major hemorrhage. (See the related article by Comin and Kallmes.)