Previous studies have demonstrated an association between increased baseline platelet counts and poorer clinical and angiographic outcomes in patients with ST-elevation myocardial infarction (STEMI). We hypothesized that antiplatelet therapy would mitigate the effect of high baseline platelet counts on clinical outcomes. Data were obtained from 3,491 patients with STEMI in the CLARITY-TIMI 28 trial. Patients were categorized into 3 groups based on their baseline platelet counts: <200 x 10(3)/microl (group 1), 200 to 300 x 10(3)/microl (group 2), and >300 x 10(3)/microl (group 3). Among placebo-treated patients, reinfarction rates increased in a stepwise fashion as platelet counts increased (3.6%, 5.4%, and 9.0%, respectively, p for trend = 0.0025). When confounders of high platelet counts and correlates of reinfarction were adjusted for in a multivariate model, high platelet counts remained independently associated with increased rates of reinfarction at 30 days in placebo-treated patients; using group 1 as a reference group, multivariate odds ratios were 1.45 (95% confidence interval 0.91 to 2.31, p = 0.119) for patients in group 2 and 1.78 (95% confidence interval 1.03 to 3.08, p = 0.038) for patients in group 3. In contrast, among clopidogrel-treated patients, there was no increase in the risk of reinfarction as the platelet count increased (3.2%, 4.1%, and 3.3%, respectively; p for trend = 0.9073, p for interaction=0.064). In conclusion, among patients with STEMI who are treated with aspirin and a fibrinolytic agent, high platelet counts on presentation are independently associated with increased rates of reinfarction. Clopidogrel therapy abolishes this increase in the risk of reinfarction as platelet counts increase. These data are consistent with a putative role of platelets in reinfarction.