The pivotal role of thrombosis in unstable angina and non-Q-wave myocardial infarction has been established recently. To assess the value and safety of thrombolytic therapy compared to conventional antithrombotic therapy (aspirin) in arresting progression in this setting to recurrent ischemic end-points, 25 patients presenting with unstable angina and an electrocardiogram showing subendocardial ischemia were randomized to receive either aspirin 325 mg daily, or urokinase 3 x 10(6) U intravenously, over 30 minutes followed by heparin. Incidence of endpoints (intractable ischemia requiring mechanical intervention, new myocardial infarction or death) was determined over 7 days. Coronary arteriography was performed at 24 to 72 hours to determine extent of coronary artery disease and morphologic severity of the culprit lesion, graded by a semiquantitative scoring system ranging from 4+ (definite thrombosis) to 0 (chronic lesion). In the first 24 hours, 7 of 13 aspirin versus 1 of 12 urokinase patients exhibited ischemia progression (p less than 0.05). By 7 days, progression to a primary ischemic endpoint occurred in 8 of 13 aspirin patients (3 myocardial infarctions and 5 intractable ischemias) versus 3 of 12 urokinase patients (2 intractable ischemias and 1 death) (p = 0.18). The apparent benefit of urokinase followed by heparin compared to conventional aspirin therapy in arresting early progression of unstable angina or non-Q-wave myocardial infarction was not associated with enhanced culprit lesion morphology (mean lesion severity score 2.7 +/- 1.5 vs 2.8 +/- 1.6 in aspirin-treated patients). Large scale, randomized trials to assess the clinical utility of urokinase for unstable angina are warranted.