Prasugrel is more potent than clopidogrel, but it is not known whether this translates into clinical benefit in patients undergoing primary percutaneous coronary intervention (PCI) with bivalirudin for ST elevation myocardial infarction. In the Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction trial, 452 patients with anterior STEMI undergoing primary PCI with bivalirudin were randomized to intralesional abciximab or placebo and to thrombus aspiration or no aspiration. Clopidogrel or prasugrel were administered at physician discretion. The primary end point was infarct size at 30 days by cardiac magnetic resonance imaging. Clinical events at 30 days and 1 year were independently adjudicated. Propensity score was used to adjust for nonrandom allocation of the drugs. Prasugrel and clopidogrel were administered to 155 patients (34.3%) and 297 patients (65.7%), respectively. Patients receiving prasugrel were younger with higher left ventricular ejection fraction and greater use of drug-eluting stents. Prasugrel-treated patients had higher rates of procedural success (94% vs 89%, p = 0.03), Thrombolysis In Myocardial Infarction (TIMI) 3 flow (95% vs 90%, p = 0.06), and lower corrected TIMI frame counts (21 ± 6 vs 23 ± 11, p = 0.008). At 30 days, infarct size was marginally lower in the prasugrel group (median [interquartile range] = 16.4% [6.5 to 20.0] vs 17.6% [8.1 to 25.7], p = 0.06). At 1 year, prasugrel group had significantly fewer deaths (1.3% vs 8.3%, p = 0.004) and fewer episodes of severe heart failure (2.0% vs 7.7%, p = 0.02). These findings persisted after propensity score adjustment. There were no significant differences in major bleeding. Stent thrombosis was 0% versus 2.5%, respectively, p = 0.054. We conclude that prasugrel was associated with improved efficacy and similar safety compared with clopidogrel in patients undergoing primary PCI with bivalirudin.