Mild impairment of left ventricular function determined echocardiographically was produced in dogs by serial intravenous administration of adriamycin (1 mg/kg/week for 10 weeks). Mild histological changes were observed including vacuolar degeneration but there was a minimal disruption of myocardial architecture (mean severity score 1.4). Ultrastructure of the heart was relatively intact but focal changes included a slight disarray of cellular structure with mitochondrial swelling and distortion, myocytolysis, sarcoplasmic reticular vacuolization, increased glycogen and lipid levels and rounding of nuclei with large condensed nucleoli. Despite involvement of the sarcoplasmic reticulum in damaged myocytes, the transverse-tubules appeared to be normal. It was felt that these changes represent an early stage of adriamycin cardiomyopathy. Ouabain binding was carried out as a test of sarcolemmal integrity. A significant increase in the total number of ouabain binding sites without a change in the dissociation constant was seen. A correlation was observed between the degree of impairment of left ventricular function and the observed increase in ouabain binding. These results support the concept of sarcolemmal membrane alteration as an early mechanism of adriamycin-induced myocardial functional impairment.