Background and objectives We sought to determine the frequency of use and association between prasugrel and outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) in clinical practice. Methods PROMETHEUS was a multicenter observational registry of acute coronary syndrome patients undergoing PCI from 8 centers in the United States that maintained a prospective PCI registry for patient outcomes. The primary end points were major adverse cardiovascular events at 90 days, a composite of all-cause death, nonfatal myocardial infarction, stroke, or unplanned revascularization. Major bleeding was defined as any bleeding requiring hospitalization or blood transfusion. Hazard ratios (HRs) were generated using multivariable Cox regression and stratified by the propensity to treat with prasugrel. Results Of 19,914 patients (mean age 64.4 years, 32% female), 4,058 received prasugrel (20%) and 15,856 received clopidogrel (80%). Prasugrel-treated patients were younger with fewer comorbid risk factors compared with their counterparts receiving clopidogrel. At 90 days, there was a significant association between prasugrel use and lower major adverse cardiovascular event (5.7% vs 9.6%, HR 0.58, 95% CI 0.50-0.67, P <0001) and bleeding (1.9% vs 2.9%, HR 0.65, 95% CI 0.51-0.83, P <001). After propensity stratification, associations were attenuated and no longer significant for either outcome. Results remained consistent using different approaches to adjusting for potential confounders. Conclusions In contemporary clinical practice, patients receiving prasugrel tend to have a lower-risk profile compared with those receiving clopidogrel. The lower ischemic and bleeding events associated with prasugrel use were no longer evident after accounting for these baseline differences.