Although it is known that thrombolytic therapy improves survival after acute myocardial infarction, it has been debated whether the speed with which coronary-artery patency is restored after the initiation of therapy further affects outcome. To study this question, we randomly assigned 2431 patients to one of four treatment strategies for reperfusion: streptokinase with subcutaneous heparin; streptokinase with intravenous heparin; accelerated-dose tissue plasminogen activator (t-PA) with intravenous heparin; or a combination of both activators plus intravenous heparin. Patients were also randomly assigned to cardiac angiography at one of four times after the initiation of thrombolytic therapy: 90 minutes, 180 minutes, 24 hours, or 5 to 7 days. The group that underwent angiography at 90 minutes underwent it again after 5 to 7 days. The rate of patency of the infarct-related artery at 90 minutes was highest in the group given accelerated-dose t-PA and heparin (81 percent), as compared with the group given streptokinase and subcutaneous heparin (54 percent, P < 0.001), the group given streptokinase and intravenous heparin (60 percent, P < 0.001), and the group given combination therapy (73 percent, P = 0.032). Flow through the infarct-related artery at 90 minutes was normal in 54 percent of the group given t-PA and heparin but in less than 40 percent in the three other groups (P < 0.001). By 180 minutes, the patency rates were the same in the four treatment groups. Reocclusion was infrequent and was similar in all four groups (range, 4.9 to 6.4 percent). Measures of left ventricular function paralleled the rate of patency at 90 minutes; ventricular function was best in the group given t-PA with heparin and in patients with normal flow through the infarct-related artery irrespective of treatment group. Mortality at 30 days was lowest (4.4 percent) among patients with normal coronary flow at 90 minutes and highest (8.9 percent) among patients with no flow (P = 0.009). This study supports the hypothesis that more rapid and complete restoration of coronary flow through the infarct-related artery results in improved ventricular performance and lower mortality among patients with myocardial infarction. This would appear to be the mechanism by which accelerated t-PA therapy produced the most favorable outcome in the GUSTO trial.