Doxorubicin, a widely used antineoplastic agent in clinical practice, has a serious side effect, as cardiotoxicity. Due to the risk of life-threatening cardiotoxicity which limits doxorubicin's therapeutic potential, diagnosis and prevention of doxorubicin-induced cardiotoxicity becomes essential. Free radicals, lipid peroxidation and antioxidant enzymes are suggested to be involved mainly in doxorubicin-induced cardiotoxicity pathogenesis. Aim of this study was the investigation of pathogenesis of doxorubicin induced cardiotoxicity and the effect of the pentoxphylline on this subject. The study was designed on three groups: the first group (n=10 young rabbit) who took 6 daily doses of intraperitoneal doxorubicine (cumulative dose 15mg/kg) for 15 days. The second group (n=10 young rabbit) who received pentoxifylline (40 mg/kg/day intraperitoneal) 24 hours before intraperitoneal doxorubicine and continued 7 days after the last dose of doxorubicine. The third group was a control group (n=7). We measured myocardial and plasma glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and malondialdehyte (MDA) activities and myocardial nitric oxide (NO) activity in our rabbit model. Serum troponin 1 (Tn 1) and creatine kinase MB (CKMB) values were tested for the assessment 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 (2.4 mU/μg) and increased MDA (0.056nmol/μg) and NO (0.13 μmol-3/μg) values. Pentoxphylline reduced doxorubicin-induced cardiotoxicity by increasing myocardial GSH-Px (5.6 mU/μg), SOD (5.56 U/μg) activities and decreasing myocardial NO (0.08 μmol-3/μg) activities. Although serum Tn I (2.4 ngr/mL in the first group) and CKMB (4123 U/mL in the first group) 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 major role in the pathogenesis of doxorubicin-induced cardiotoxicity and pentoxphylline is an effective antioxidant in reducing doxorubicin-induced cardiotoxicity.