The effect of reduced glutathione (GSH) on acute myocardial toxicity due to doxorubicin (DXR) was investigated. At 20 mg/kg i.p. DXR was 100% lethal to BALB/c X DBA/2 F1 mice. At 500 or 1000 mg/kg i.p. GSH significantly decreased the lethality (P less than 0.01). Electron micrographs of the myocardium from DXR-treated mice showed narrowing of myofibrils, edematous cytoplasm, and mitochondrial swelling which were detectable at day 2, was strongest at day 14, but had disappeared by day 56. Light microscopic examination revealed that intercellular spaces between myocardial cells were widened at day 56, indicating shrinking of myocardial cells. These changes were significantly decreased by treatment with GSH (500 mg/kg i.p.). Treatment with DXR (14 mg/kg) significantly decreased myocardial non-protein sulfhydryl content (P less than 0.02) and administration of GSH (500 mg/kg) prevented the drop of non-protein sulfhydryl levels due to DXR treatment. Thus it was considered that administration of exogenous GSH contributes to prevention of the acute myocardial toxicity of DXR by increasing extracellular GSH levels and intracellular GSH synthesis, which detoxifies DXR-oxygen metabolites. The administration of GSH did not interfere with the antineoplastic effect of DXR against L1210 mouse leukemia.