Background and Objectives: Protein kinase B (PKB)/Akt is a key player in numerous physiological and pathophysiological processes such as cell growth, cell survival, angiogenesis. This study was performed to elucidate the role of PKB/Akt in EPC homing. Methods and Results: In in vitro analysis, we found that the supernatant obtained from cultured skeletal muscle cells in hypoxic condition induced the overexpression of phospho-Akt and intercellular adhesion molecule-1 (ICAM-1) in endothelial cells, which was blocked with adenovirus (Av)-dnAkt (dominant-negative mutant of Akt) transfer. The role of PKB/Akt in EPC homing was evaluated in a mouse hindlimb ischemia model. After the induction of ischemia, we found that the expression of phospho-Akt was increased in ischemic muscle, which increased ICAM-1 expression subsequently. To investigate the role of PKB/Akt in vivo, Av-Green fluorescent protein (GFP), Av-myrAkt (myristoylated constitutively active form of Akt), Av-dnAkt were transferred into ischemic hindlimb muscle of mice with concomitant transplantation of EPC. The activation of the PKB/Akt by Av-myrAkt in ischemic muscle resulted in the overexpression of ICAM-1 and significant augmentation of EPC homing (n=18, ischemic/non-ischemic ratio in Laser Doppler Perfusion Image, Av-GFP versus Av-myrAkt versus Av-dnAkt = 2.5 짹 0.7, 3.2 짹 1.1, 1.6 짹 0.7, p < 0.05) and limb salvage (Av-GFP versus Av-myrAkt versus Av-dnAkt = 2/8, 5/8, 0/8). Conversely, the inactivation by Av-dnAkt resulted in the opposite. Conclusions: We found the activation of PKB/Akt augmented EPC homing through ICAM-1 in ischemic tissue. Our findings suggest that the modulation of PKB/Akt may be used as a therapeutic target to improve the efficacy of stem cell therapy.