Objectives: Doxorubicin (DOX) is a powerful anthracycline anti-cancer effects in human. Its clinical use is limited because of severe cardiotoxic side effects. Glucagon-like Peptide-1 (GLP-1) analogue, exenatide, alleviates myocardial injury caused by ischemia-reperfusion and TG9 dilated cardiomyopathy model. The aim of this study was to evaluate that simultaneous exenatide treatment protects against DOX-induced cardiomyopathy by improving ventricular function and cell death. Methods: Adult Sprague-Dawley rats were given a six dose of doxorubicin (total 15 mg/kg intraperitoneally) for DOX-induced cariomyopathy during 2 weeks. To investigate the novel role of exenatide in DOX-induced CMP, exenatide (Byetta짰 Lilly) was injected subcutaneously one hour prior to every DOX injection. Left ventricular systolic and diastolic function, chamber morphology using both echocardiography and pressure-volume Millar catheterization were assessed 28 days after 1st injection. Isolated hearts were examined the anti-apoptotic roles of exenatide by TUNEL analysis, immunoblot for Caspase-3, Bax and Bcl-2. Cardiomyocyte necrosis and apoptosis were assessed. In addition, morphologic and property analysis of mitochondria by atomic force microscopy (AFM). Results: Doxorubicin caused impairment of ventricular systolic and diastolic function and cell death, which were significantly reduced by exenatide injection (p<0.05). Left ventricular dimension at diastole was decreased (exenatide vs. control, 6.87 짹 0.6 mm vs. 9.6짹6.8, p<0.01) as compared to untreated rats. The number of TUNEL positive cells and active caspase-3 level were slightly decreased by exenatide treatment compared with untreated group. Enhanced Bax expression by DOX treatment was suppressed in the exenatide treated group. These cardioprotective effects were associated with a significant decrease in tissue lipid peroxidation. Area and shape parameters of mitochondria in AFM image will be presented. Conclusions: Simultaneous exenatide treatment attenuates DOX-induced ventricular dysfunction, cell death, oxidative stress. Exenatide may be a therapeutic agent against DOX-induced cardiotoxicity.