Insulin-like growth factors (IGFs) are mediators of growth hormone-induced metabolic and anabolic actions, but also regulate cell growth, differentiation, and apoptosis and show beneficial effects in acute myocardial ischemia. Since endothelial progenitor cells (EPCs) improve myocardial function after acute myocardial infarction, we sought to investigate whether overexpression of IGF-2 in expanded EPCs (eEPCs) further contributes to improvement in left ventricular function after myocardial infarction. EPCs were isolated from human cord blood and transduced by a retroviral vector expression of IGF-2 (IGF-2 eEPCs) or vector only. Expression levels were confirmed by RT-PCR. Vector only-transduced eEPCs or IGF-2 eEPCs were transplanted after ligation of the left anterior descending coronary artery in athymic nude rats. Transplantation of eEPCs improved the left ventricular ejection fraction after 2 weeks. Overexpression of IGF-2 further improved the left ventricular ejection fraction and reduced the myocardial infarction size. Immunohistological analysis revealed an increase in proliferating cells and a decrease in monocytes and apoptotic myocytes within the infarction zone after transplantation of IGF-2-overexpressing eEPCs. Transplantation of IGF-2-overexpressing eEPCs in acute myocardial infarction may improve early myocardial function by enhancing proliferation and limiting the inflammatory response and apoptosis.