Previous studies describing the no-reflow phenomenon in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) were largely confined to single-center studies or small registries. To better characterize the incidence, predictors, and outcomes of the no-reflow phenomenon in a large contemporary population, we analyzed patients with AMI who were undergoing PCI of native coronary artery stenoses in the CathPCI Registry from January 1, 2004 through September 5, 2008 (n = 291,380). The angiographic no-reflow phenomenon was site reported using a standardized definition. No-reflow developed in 2.3% of the patients with AMI (n = 6,553) during PCI. Older age, ST-segment elevation AMI, prolonged interval from symptom onset to admission, and cardiogenic shock were clinical variables independently associated with the development of no-reflow (p <0.001). The angiographic factors independently associated with no-reflow included longer lesion length, higher risk class C lesions, bifurcation lesions, and impaired preprocedure Thrombolysis In Myocardial Infarction flow (p <0.001). No-reflow was associated with greater in-hospital mortality (12.6% vs 3.8%, adjusted odds ratio 2.20, 95% confidence interval 1.97 to 2.47, p <0.001) and unsuccessful lesion outcome (29.7% vs 6.6%, adjusted odds ratio 4.70, 95% confidence interval 4.28 to 5.17, p <0.001) compared to patients without no-reflow. In conclusion, the development of no-reflow, although relatively uncommon during PCI for AMI, is associated with adverse clinical outcomes. Upfront strategies to reduce the incidence of no-reflow could be considered for high-risk patients to improve outcomes.