Adriamycin (doxorubicin) is an antineoplastic drug used to treat various cancers; however, its chronic use is accompanied by cardiotoxicity. Previous results suggested that free radical formation may contribute to Adriamycin toxicity. Adriamycin-induced cardiotoxicity was examined in rats maintained on either standard or selenium-supplemented diets. Adriamycin was administered intraperitoneally; the cumulative dose was 15 mg/kg body weight. Selenium status, glutathione peroxidase activities, vitamin E, and MDA contents were determined on red blood cell (RBC) and cardiac homogenates. RBC selenium levels and selenium glutathione peroxidase activity were significantly increased in selenium-supplemented animals compared with control or placebo groups. However, Adriamycin-treated rats showed a significant decrease in RBC selenium and selenium glutathione peroxidase compared with the placebo group. Moreover, treatment with Adriamycin increased RBC MDA content, which was attenuated by the selenium supplementation. In parallel, RBC vitamin E decreased markedly in the Adriamycin-treated group and was totally restored by selenium supplementation. Cardiac biochemical analyses confirmed the blood results. Thus, a free radical mechanism does contribute to Adriamycin cardiotoxicity, and shows the importance of balancing selenium levels in Adriamycin-treated subjects to limit Adriamycin's action. A decrease in Adriamycin cardiotoxicity with no concomitant decrease in its antineoplastic activity would considerably improve the therapeutic benefit of the drug.