Adriamycin (ADR) is a useful antitumor agent but causes severe cardiotoxicity requiring dose limitation. Methylprednisolone (MP) has been shown to stabilize cell membranes and, in ischemic heart models, to protect mitochondria lysosomes and sarcolemma. The purpose of this study was to determine if MP could prevent ADR-induced cardiotoxicity in rats. Twenty-eight normal, male, Wistar rats were placed in two groups of 14 each. One group received ADR 2 mg/kg iv weekly for 3 weeks, followed by 2 mg/kg subcutaneously weekly. The other group received the same dosage of ADR but also MP 20 mg/kg subcutaneously 3 hr before, with ADR and 3 hr after ADR. Seven rats in each group were sacrificed after the 10th week of treatment. At autopsy 7/7 (100%) of the rats in the ADR groups had obvious ascites and pleural effusion whereas 0/7 in the ADR + MP group developed this complication (P less than 0.01). Microscopic examination of the hearts revealed vacuole formation, loss of muscle mass, tapering off of myocardial cells, or inflammatory changes in 7/7 (100%) of the rats in the ADR group and in 2/7 (28%) of the ADR and MP group (P less than 0.05). Among the rats left to monitor survival, at 11 weeks from the initiation of treatment, 4/7 (57%) in the ADR group and 7/7 (100%) in the ADR + MP group were alive. These data indicate that MP provides some protection from Adriamycin-induced cardiotoxicity in rats.