The clinical usage of antineoplastic drug doxorubicin (DOX) is limited due to cardiotoxic side effects. The cytokine erythropoietin (EPO) is critical for the production of mature red blood cells and is commonly used to treat anemia in cancer therapy. Recent experimental data reported that EPO contributes to anti-apoptosis in neuronal, vascular smooth muscle, and vascular endothelial cells. I examined whether EPO protects the heart against DOX-induced cardiomyopathy. EPO protected cultured neonatal mouse ventricular myocytes (NMVMs) against DOX-induced cell death and apoptosis. This protection by EPO correlated with increased phosphorylation of PI3K-dependent survival pathways, Akt/PKB and GSK-3beta while PI3K inhibitor LY294002 diminished EPO's protective effects. These protective actions of EPO were also observed in mice administered DOX wherein cardiac function, as assessed using echocardiography. Conclusion. This study suggests that EPO protects myocardium against DOX-induced apoptotic cell death via PI3K-dependent pathways as well as impaired heart function.