A model of coronary artery thrombosis which: (1) provides a stable thrombus; (2) incorporates intimal injury; (3) has a low mortality rate; (4) responds predictably to thrombolytic therapy, and (5) is technically simple, was developed. Intimal injury was produced proximal to a critical stenosis and followed by the infusion of a blood and thrombin mixture into the injured segment. After thrombus formation flow remained absent in all control animals (n = 7). Microscopy showed intimal injury and coronary thrombosis with platelets adherent to the subendothelium. In animals treated with tissue plasminogen activator (n = 7) flow returned to > 60% of baseline at 20.2 ± 7.7 min and was cyclical. Mortality and complications were infrequent. This model is useful in investigations of reperfusion therapy.