Background Studies have shown sex‐based disparities in ST‐segment elevation myocardial infarction (STEMI) management and prognosis. We sought to compare women and men undergoing primary percutaneous coronary intervention (PCI) for STEMI in a large, prospective, contemporary context. Methods The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS‐AMI) trial randomized 3,602 patients (23.4% women and 76.6% men) with STEMI presenting within 12 hr of onset of symptoms to bivalirudin or heparin plus glycoprotein IIb/IIIa inhibitors and to PCI with drug‐eluting or bare metal stents. Results Compared with men, women presented later after symptom onset and were more often treated with medical management alone (6.9% vs. 4.7%; P = 0.01). Women had significantly higher rates of 3‐year major adverse cardiac events (MACE) and major bleeding. After adjusting for baseline differences, female sex remained an independent predictor of major bleeding (hazard ratio HR 1.81, 95% confidence interval CI 1.41–2.33; P < 0.0001) but not of MACE (HR 1.09; 95% CI 0.91–1.32; P = 0.35). Conclusions This study found that women with STEMI are at increased risk of bleeding as compared to men. While female sex may not directly contribute to increased risk of MACE, it is, however, associated with the presence of comorbidities that increase the risk of ischemic events long‐term. Further dedicated studies are needed to confirm these findings and to assess strategies to optimize both the initial emergent treatment and long‐term management in this high‐risk subset. © 2014 Wiley Periodicals, Inc.