Doxorubicin, a widely used antineoplastic agent in clinical practice, has a serious side effect, cardiotoxicity. Due to the risk of life-threatening cardiotoxicity which limits doxorubicin’s therapeutic potential, diagnosis and prevention of doxorubicin-induced cardiotoxicity become essential. Free radicals, lipid peroxidation and antioxidant enzymes are suggested to be mainly involved in doxorubicin-induced cardiotoxicity pathogenesis. The aim of this study was evaluation of the pathogenesis of doxorubicin-induced cardiotoxicity and the effect of melatonin. The study was designed with three groups: in the first group (n=10 young rabbits) doxorubicin was administered in six equal intraperitoneal injections over a period of two weeks (cumulative dose 15 mm/ kg). The second group (n=7 young rabbits) who received melatonin (10 mg/ kg/day intraperitoneally) 24 hours before intraperitoneal doxorubicin, and it was continued seven days after the last dose of doxorubicin. The third group was the control group (n=7). We measured myocardial and plasma glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and malondialdehyde (MDA) activities and myocardial nitric oxide (NO) activity in our rabbit model. Serum troponin I (Tn I) and creatine kinase (CK-MB) values were tested for diagnostic value of cardiotoxicity. Our results suggested that doxorubicin formed severe cardiotoxicity in young rabbits with 15 mg/kg cumulative doses with markedly decreased myocardial GSH-Px and increased MDA and NO values. Melatonin reduced doxorubicin-induced cardiotoxicity by increasing myocardial GSH-Px and SOD activities. Although serum Tn I and CK-MB levels had diagnostic values, any change in plasma GSH-Px, SOD and MDA activities was determined in assessing doxorubicin-induced cardiotoxicity. In conclusion, decreased antioxidant enzyme levels, increased free radicals and lipid peroxidation play a major role in the pathogenesis of doxorubicin-induced cardiotoxicity, and melatonin is an effective antioxidant in reducing doxorubicininduced cardiotoxicity. Anahtar Kelimeler : doksorubisin, nitrik oksit, glutatyon peroksidaz, malondialdehit, melatonin,doxorubicin, nitric oxide, glutathione peroxidase, malondialdehyte, melatonin.