Background and Objective; Recent studies suggest protective effects of erythropoietin (EPO) protein against doxorubicin-induced cardiotoxicity. However, EPO protein therapy requires large dose and frequent administration. We assessed the hypotheses that the human endothelial progenitor cell (hEPC) is efficient compared to HeLa cell as a gene- delivered vehicle, and EPO gene therapy using hEPC infected lentivirus (hEPC/Lent-EPO) is also safe and feasible in a rat model of doxorubicin-induced cardiotoxicity. Methods; Recombinant lentiviral vectors containing the rat EPO gene were made by cotransfection of 293T cell with pRRL-cPPT-CMV-EPO-PRE-SIN, pMDL, pVSVG, and pREV plasmid. We identified and Lenti-GFP expression and measured EPO levels at the supernatant of hEPC/Lent-EPO and HeLa/Lenti-EPO. Male Sprague Dawley rats (8 weeks of age, n=15) were given 5mg/kg of doxorubicin (DOX) intravenously 3 times over a 2-week period (15mg/kg) to induce cardiotoxicity. hEPC and hEPC/Lenti-EPO groups were evaluated for the effect of Lenti-EPO (A; DOX, B; DOX+hEPC/Lenti-GFP, C; DOX+hEPC/Lenti-EPO, each group; n=5). DAPI-labeled hEPC (1x10⁶ cells) infected Lenti-GFP and Lenti-EPO were used at 1 and 3 weeks. Echocardiographic analysis and histological analysis including apoptosis by TUNEL staining were evaluated at 4 weeks. Results; The GFP expression of hEPC was similar with that of HeLa cell. However, In EPO level hEPC was higher than that of HeLa cell (72 hours after infection; 126 vs 90 mU/mL). In animal, the EPO level at hEPC/Lenti-EPO was consistently increased for 2 weeks compared to hEPC/Lenti-GFP. All animals in hEPC treated groups, both hEPC/Lenti-GFP and hEPC/Lent-EPO, were survived without any complication. Although overt heart failure was not fully developed at 4 weeks, the apoptosis of cardiomyocytes was inhibited at hEPC/Lenti-EPO than hEPC/Lenti-GFP. Conclusion; hEPC is efficient cell source as a gene-delivered vehicle compared to HeLa cell, and Lenti-EPO gene therapy using hEPC is also safe and feasible. These findings suggest that hEPC-mediated Lenti-EPO gene therapy has considering potential as an effective treatment.