Background: The combination of fibrinolytic therapy and heparin for acute myocardial infarction fails to achieve reperfusion in 40-70% of patients, and early reocclusion occurs in a substantial number. We did a randomised, open-label trial to compare the thrombin-specific anticoagulant, bivalirudin, with heparin in patients undergoing fibrinolysis with streptokinase for acute myocardial infarction. Methods: 17 073 patients with acute ST-elevation myocardial infarction were randomly assigned an intravenous bolus and 48-h infusion of either bivalirudin (n=8516) or heparin (n=8557), together with a standard 1.5 million unit dose of streptokinase given directly after the antithrombotic bolus. The primary endpoint was 30-day mortality. Secondary endpoints included reinfarction within 96 h and bleeding. Strokes and reinfarctions were adjudicated by independent committees who were unaware of treatment allocation. Analysis was by intention to treat. Findings: By 30 days, 919 patients (10.8%) in the bivalirudin group and 931 (10.9%) in the heparin group had died (odds ratio 0.99 [95% CI 0.90-1.09], p=0.85). The mortality rates adjusted for baseline risk factors were 10.5% for bivalirudin and 10.9% for heparin (0.96 [0.86-1.07], p=0.46). There were significantly fewer reinfarctions within 96 h in the bivalirudin group than in the heparin group (0.70 [0.56-0.87], p=0.001). Severe bleeding occurred in 58 patients (0.7%) in the bivalirudin group versus 40 patients (0.5%) in the heparin group (p=0.07), and intracerebral bleeding occurred in 47 (0.6%) versus 32 (0.4%), respectively (p=0.09). The rates of moderate and mild bleeding were significantly higher in the bivalirudin group than the heparin group (1.32 [1.00-1.74], p=0.05; and 1.47 [1.34-1.62], p<0.0001; respectively). Transfusions were given to 118 patients (1.4%) in the bivalirudin group versus 95 patients (1.1%) in the heparin group (1.25 [0.95-1.64], p=0.11). Interpretation: Bivalirudin did not reduce mortality compared with unfractionated heparin, but did reduce the rate of adjudicated reinfarction within 96 h by 30%. Small absolute increases were seen in mild and moderate bleeding in patients given bivalirudin. Bivalirudin is a new anticoagulant treatment option in patients with acute myocardial infarction treated with streptokinase.