The cardiotoxicities of 4'-epidoxorubicin (4-epiDX) and doxorubicin (DX) were compared in rabbits. Thirty-one male NZW rabbits weighing 2.4 to 2.6 kg were used for each compound and 15 were kept as controls. DX or 4'-epiDX was administered intravenously with a dose of 0.8 mg/kg for 3 consecutive days a week for 5-10 weeks. Rabbits were sacrificed at 5, 8 and 10 weeks after initial administration. Under nembutal anesthesia, electrocardiogram, phonocardiogram and carotidgram were recorded. Light and electron microscopic studies of the heart were performed according to conventional methods. Myocardial alterations were semi-quantitatively evaluated with light microscopy, using a modified grading system derived from Bertazzoli. Twelve of the DX-treated rabbits and 4 of the 4'-epiDX-treated rabbits died after 5 weeks or later. In the electrocardiogram study, ST-T changes were less frequently observed in rabbits treated with 4'-epiDX than those with DX. Significant increases of PEP/LVET were observed in rabbits treated with DX for 8 and 10 weeks, similar increases were only observed while in rabbits treated with 4'-epiDX for 10 weeks. Histologically, both drugs produced myocardial degeneration and necrosis. The lesions were characterized by multiple vacuolization of myocardial cells, atrophy of myocardial cells, interstitial edema and fibrosis. Myocardial alterations induced by 4'-epiDX were qualitatively similar to those induced by DX, but were much less severe at the same cumulative dose. These results demonstrate that 4'-epiDX is less cardiotoxic than DX.