Objectives. This study was designed to determine whether maintenance of patency in coronary arteries with high grade stenosis after thrombolysis with tissue-type plasminogen activator requires inhibition of thrombin or platelets, or both. Background. Activation of both thrombin and platelets has been implicated in delaying coronary recanalization induced with fibrinolytic drugs and in predisposing to reocciusion. Methods. Hirudin (1.5 mg/kg body weight) or aspirin (5 mg/kg), or both, was given conjunctively with tissue-type plasminogen activator in 28 conscious dogs with coronary thrombosis induced by electrical stimulation of the vessel wall in the presence of a previously placed high grade distal stenosis (85 ± 12% [SEM] area reduction). Results. Among 22 dogs exhibiting coronary recanalization, hirudin plus aspirin, but neither agent alone, modestly shortened the interval to recanalization (31 ± 4 min with saline solution, n 6; 29 ± 4 min with aspirin, n = 5; 23 ± 9 min with hirudin, n = 6; 21 ± 7 min with hirudin + aspirin, n = 5). Reocclusion occurred promptly and persisted in five of six dogs given only saline solution plus tissue-type plasminogen activator, in four of six dogs given hirudin and five of five dogs given aspirin; however, reocclusion was prevented in all five of the dogs given both hirudin and aspirin with tissue-type plasminogen activator (p < 0.05 compared with saline-treated dogs). In dogs given both hirudin and aspirin, the partial thromboplastin time was 2.4 ± 0.3 times baseline, and the template bleeding time was prolonged only modestly (1.6 ± 0.3 baseline). Conclusions. Thus, the combination of hirudin and aspirin in doses that do not markedly perturb hemostasis prevents early reocciusion after thrombolysis despite the presence of severe stenosis. Accordingly, conjunctive administration of both antithrombin and antiplatelet agents appears to be necessary for optimal maintenance of patency after thrombolysis induced in the presence of high grade coronary stenosis.