Endothelial progenitor cells (EPCs) have been reported to significantly contribute to the neovessel formation at ischemic tissues. However, there has been limited knowledge regarding what factors play important roles in EPC-mediated neovascularization. Recent studies have been shown that angiopoietin2 (Ang2) is highly upregulated at ischemic tissues and also its plasma level is significantly elevated in patients with ischemic heart diseases. This strong expression of Ang2 at hypoxic milieu prompted us to hypothesize that Ang2 might play a role in EPC-mediated neovascularization at sites of ischemia. Here we found that Ang2 (200 ng/ml) promoted the cell survival, migration, and tube formation in human cord blood-derived EPCs, although Ang2 had no such effect in mature endothelial cells at the same concentration. This proangiogenic activity of Ang2 in EPCs was inhibited by the pretreatment of EPCs with anti-Tie2 antibody, indicating that Ang2 enhanced the angiogenicity of EPCs through Tie2 receptors. Indeed, western blotting experiment showed that Ang2 rapidly phosphorylated Tie2 receptors within 15 minutes, and subsequently activated the Tie2 downstream signaling molecules, such as Akt and endothelial nitric oxide synthase in EPCs, as has been demonstrated in angiopoietin1. Although Ang2 has been known as an antagonist of angiopoietin1 in the interaction with Tie2 receptors, our findings demonstrate for the first time that Ang2 directly activates Tie2 signaling pathway in EPCs and plays proangiogenic roles in EPC-mediated vascular biology. In addition, this result provides an important pathophysiological implication regarding Ang2 expression at ischemic tissues in terms of EPC-mediated neovascularization.