The predictors of improvement in left ventricular ejection fraction (LVEF) after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) are poorly understood. We sought to determine the prevalence and clinical and angiographic predictors of LVEF improvement after primary PCI in STEMI. In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction trial, 3,602 patients presenting with STEMI were randomized to heparin + a glycoprotein IIb/IIIa inhibitor versus bivalirudin. Routine 13-month angiographic follow-up was performed in a prespecified substudy of 656 stented patients. The median [25%, 75%] change in LVEF from baseline to 13 months was +2.4% [−5.9%, 11.8%]; LVEF increased or remained unchanged in 379 patients (57.8%; median Δ +9.8% [4.3%, 16.4%]) and fell in 277 patients (42.2%; median Δ −7.0% [−11.8%, −3.6%]). Independent predictors of LVEF improvement were female gender (p = 0.002), lower baseline LVEF (p <0.0001), Thrombolysis in Myocardial Infarction 3 flow after PCI (p = 0.03), shorter lesion length (p = 0.04), and lower post-PCI peak MB isoenzyme of creatine kinase (p <0.0001). In conclusion, in the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction trial, although LVEF improved during follow-up after primary PCI in more than half of patients, left ventricular function worsened over time in a substantial proportion, the occurrence of which may be predicted by clinical, angiographic, and laboratory variables.