Background Little is known about the use of platelet function testing to guide choice of P2Y12 receptor inhibitor therapy in routine clinical practice. Methods We studied 671 myocardial infarction (MI) patients treated with percutaneous coronary intervention in the TRANSLATE-ACS Registry who had VerifyNow platelet function testing performed while on clopidogrel treatment during their index hospitalization (April 2010–October 2012). Results High platelet reactivity (>208 platelet reactivity units [PRU]) was present in 261 (38.9%) patients. Clopidogrel was switched in-hospital to prasugrel in 80 (30.7%) patients with high platelet reactivity and 18 (4.4%) patients with therapeutic platelet reactivity (≤208 PRU). Among high platelet reactivity patients, switch to prasugrel was associated with lower major adverse cardiovascular events (death, MI, stroke, or unplanned revascularization) at 1 year (10.0% vs 22.7%, P = 02 adjusted odds ratio [OR] 0.39, 95% CI 0.18-0.85, P = 02) and no significant difference in Bleeding Academic Research Consortium type 2 or higher bleeding (23.8% vs 22.1%, P = 77 adjusted OR 0.91, 95% CI 0.48-1.7, P = 77) compared with patients continued on clopidogrel. No significant differences in major adverse cardiovascular event (22.2% vs 12.8%, P = 25 adjusted OR 1.8, 95% CI 0.47-7.3, P = 38) or bleeding (22.2% vs 19.4%, P = 77 adjusted OR 1.3, 95% CI 0.27-6.8, P = 72) were observed among therapeutic platelet reactivity patients between switching and continuation on clopidogrel. Conclusions Only one-third of percutaneous coronary intervention–treated MI patients with high on-clopidogrel platelet reactivity were switched to a more potent P2Y12 receptor inhibitor. Intensification of antiplatelet therapy was associated with lower risk of ischemic events at 1 year among HPR patients.