OBJECTIVES: To understand the optimal timing of adenosine diphosphate (ADP) receptor inhibitor pretreatment prior to percutaneous coronary intervention (PCI) among acute myocardial infarction (MI) patients. BACKGROUND: The role of ADP receptor inhibitor pretreatment in this population is unclear. METHODS: A total of 9,251 ADP receptor inhibitor-naïve MI patients undergoing PCI at 229 TRANSLATE-ACS sites were evaluated. Adjusted risks of in-hospital major adverse cardiovascular events (MACE) and major bleeding were compared among patients with and without pretreatment using inverse probability-weighted propensity adjustment. RESULTS: Of 9,251 patients treated with either prasugrel or clopidogrel during the index MI hospitalization, 4,056 (44%) received pretreatment (ST-segment elevation MI [STEMI] 54.9%, non-STEMI 45.1%); pretreatment was used more commonly among those receiving clopidogrel than prasugrel (52% vs. 20%, P < 0.0001). MACE risks were not significantly different between patients with and without pretreatment (clopidogrel 2.1% vs. 2.2%, adjusted hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.70-1.43; prasugrel 2.1% vs. 2.3%, adjusted odds ratio [OR] 0.82, 95% CI 0.42-1.60). No differences in major bleeding were observed among those receiving versus not receiving pretreatment (clopidogrel 3.1% vs. 3.5%, adjusted HR 0.94, 95% CI 0.65-1.36; prasugrel 2.5% vs. 2.7%, adjusted OR 0.93, 95% CI 0.42-2.02); results were similar when stratified by MI type. CONCLUSIONS: ADP receptor inhibitor pretreatment (44%) is commonly used among acute MI patients undergoing PCI in contemporary practice, but no significant differences were found in in-hospital MACE and/or bleeding risks between patients receiving versus not receiving pretreatment, regardless of ADP receptor inhibitor type.