Importance: The safety and efficacy of bivalirudin compared with heparin with or without glycoprotein IIb/IIIa inhibitors in patients with acutemyocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) are uncertain. OBJECTIVE To determine if bivalirudin is superior to heparin alone and to heparin plus tirofiban during primary PCI. Design, Setting, and Participants: Multicenter, open-label trial involving 2194 patients with AMI undergoing primary PCI at 82 centers in China between August 2012 and June 2013. Interventions: Patients were randomly assigned to receive bivalirudin with a post-PCI infusion (n = 735), heparin alone (n = 729), or heparin plus tirofiban with a post-PCI infusion (n = 730). Among patients treated with bivalirudin, a postprocedure 1.75mg/kg/h infusion was administered for a median of 180 minutes (IQR, 148-240 minutes). Main outcomes and Measures: The primary end pointwas 30-day net adverse clinical events, a composite of major adverse cardiac or cerebral events (all-cause death, reinfarction, ischemia-driven target vessel revascularization, or stroke) or bleeding. Additional prespecified safety end points included the rates of acquired thrombocytopenia at 30 days, and stent thrombosis at 30 days and 1 year. Results: Net adverse clinical events at 30 days occurred in 65 patients (8.8%) of 735 who were treated with bivalirudin compared with 96 patients (13.2%) of 729 treated with heparin (relative risk [RR], 0.67; 95%CI, 0.50-0.90; difference, -4.3%, 95%CI, -7.5%to -1.1%; P = .008); and 124 patients (17.0%) of 730 treated with heparin plus tirofiban (RR for bivalirudin vs heparin plus tirofiban, 0.52; 95%CI, 0.39-0.69; difference, -8.1%, 95%CI, -11.6%to -4.7%; P < .001). The 30-day bleeding rate was 4.1%for bivalirudin, 7.5%for heparin, and 12.3%for heparin plus tirofiban (P < .001). There were no statistically significant differences between treatments in the 30-day rates of major adverse cardiac or cerebral events (5.0%for bivalirudin, 5.8% for heparin, and 4.9% for heparin plus tirofiban, P = .74), stent thrombosis (0.6%vs 0.9%vs 0.7%, respectively, P = .77), acquired thrombocytopenia (0.1%vs 0.7%vs 1.1%; P = .07), or in acute (<24-hour) stent thrombosis (0.3%in each group). At the 1-year follow-up, the results remained similar. Conclusions and Relevance: Among patients with AMI undergoing primary PCI, the use of bivalirudin with a median 3-hour postprocedure PCI-dose infusion resulted in a decrease in net adverse clinical events compared with both heparin alone and heparin plus tirofiban. This finding was primarily due to a reduction in bleeding events with bivalirudin, without significant differences in major adverse cardiac or cerebral events or stent thrombosis.