Patients with prior coronary bypass surgery with acute ST-segment elevation myocardial infarction (MI) pose an increasingly common clinical problem. We assessed the characteristics and outcomes of such patients undergoing thrombolysis for acute MI. We compared the characteristics and outcomes of patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial (GUSTO-I) who had had prior bypass (n = 1784, 4% of the population) with those without prior coronary artery bypass grafting (CABG), all of whom were randomized to receive one of four thrombolytic strategies. Patients with prior bypass were older with significantly more prior MI and angina. Overall, 30-day mortality was significantly higher in patients with prior bypass (10.7% vs 6.7% for no prior bypass, P <.001); these patients also had significantly more pulmonary edema, sustained hypotension, or cardiogenic shock. Patients with prior bypass showed a 12.5% relative reduction (95% confidence interval, 0% to 41.9%) in 30-day mortality with accelerated alteplase over the streptokinase monotherapies. In the 62% of patients with prior CABG who underwent coronary angiography, the infarct-related vessel was a native coronary artery in 61.9% and a bypass graft in 38.1% of cases. The Thrombolysis in Myocardial Infarction (TIMI) 3 flow rate was 30.5% for culprit native coronary arteries and 31.7% for culprit bypass grafts. Patients with prior bypass had more severe infarct-vessel stenoses (99% [90%, 100%] vs 90% [80%, 99%], P <.001). The 30-day mortality in patients with prior CABG was significantly higher than that for patients without prior CABG. As in the overall trial, these patients derived an incremental survival benefit from treatment with accelerated alteplase, but mortality remained high (16.7%) at 1 year. These results are at least partially explained by the higher baseline risk of these patients and by the lower rate of patency of the infarct-related artery.