Doxorubicin (DXR) is a common antineoplastic agent whose clinical utility is limited by development of a dose-related cardiomyopathy. Recent studies demonstrating DXR toxicity in skeletal muscle suggest that this compound may in fact be a general depressant of muscle function. Although previous studies have reported possible indirect actions of DXR on blood vessels, we have investigated the direct effects of this agent on vascular smooth muscle. Chronic, low-dose treatment of rats with intraperitoneal DXR (12 mg/kg total dose over 4 weeks) had no significant effect on body or heart weight, left ventricular water or calcium content, or aortic water or calcium content. Contractile responses to norepinephrine of thoracic aortic strips taken from DXR-treated rats were attenuated by this treatment, and sensitivity (EC50) of these strips to norepinephrine was significantly reduced compared to controls. These results suggest that DXR may have physiological effects on vascular smooth muscle function at doses which produce no signs of toxicity in cardiac muscle.