Summary Patients with coronary artery disease and severe angina pectoris refractory to conventional medical treatment (beta-blockers, nitrates, calcium antagonists) and without the option for invasive revascularization procedures, present an increasing clinical problem. For these patients, chronic-intermittent urokinase therapy has been developed as a combined rheological and thrombolytic approach to the improvement of myocardial perfusion. In chronic-intermittent urokinase therapy 500,000 IU of urokinase are applied 3 times a week over a period of 12 weeks as an intravenous bolus injection. The target fibrinogen level, which is the major determinant of rheological blood properties (plasma viscosity, red blood cell aggregation) in microcirculation should range between 200 and 250 mg/dl. Reductions of fibrinogen levels amount to an average of about 35%, with subsequent reductions of plasma viscosity (approx. −7%) and red blood cell aggregation (approx. −18%). These changes are accompanied by significant reductions of clinical symptoms (anginal events/week) by approximately 75% from initially 23 ± 12 events/week; the clinical therapeutic effect is achieved after 2–4 weeks of treatment. Apart from the clinical improvements, objective signs of myocardial ischemia during ergometric exercise testing — such as ‘average negative ST-segment deviation’, ‘endpoint at termination of exercise’ and ‘exercise time to angina pectoris and/or to negative ST-segment deviation > 0.1mV’ — change favorably after treatment. A dose-response study which compared the application of 3 × 50,000 IU/week (n = 49) with 3 × 500,000 IU/week (n = 49) in patients with refractory angina pectoris could demonstrate a beneficial dose-dependent clinical effect for the higher dosage, which seems to be closely related to the reductions of the fibrinogen levels. There was no cumulation of undesirable side effects like an increase of coronary ischemic events and bleeding complications in the high-dose group. After termination of therapy with 3 × 500,000 IU urokinase/week (n = 121), the therapeutic effect (reduction of anginal events > 66%/week) lasted for 13.9 ± 8.6 months during a follow up period of 19.3 ± 10 months. Conclusion: Chronic-intermittent urokinase therapy in a dosage of 3 × 500,000 IU/week over a period of 12 weeks represents an effective antiischemic and antianginal approach in patients with refractory angina pectoris and end-stage coronary artery disease.