Objective：To investigate the effects of tumor necrosis factor-like attenuated apoptosis factor（TWEAK）mediated by Fn14-PI3K-Akt signaling pathway on the proliferation，migration and angiogenesis of human umbilical cord blood derived human endothelial progenitor cells（hEPCs）. Methods：hEPCs were isolated and identified in vitro. The hEPCs were treated with Fn14 siRNA and LY294002（LY），a specific inhibitor of PI3K. The cells were divided into the control group，the TWEAK treatment group，the TWEAK + Fn14 siRNA blocking group and the TWEAK + LY treatment group. Cell proliferation was measured by CCK-8 assay，cell migration assay was performed in Transwell chamber，and angiogenesis ability was evaluated by Matrigel tubule formation assay. The expressions of p-Akt and T-Akt in cell lysate were measured by Western blot. Results：The hEPCs cultured in vitro showed that TWEAK significantly promoted the proliferation and migration of hEPCs and enhanced the vascularization ability of hEPCs. However，the proliferation，migration and angiogenesis ability of hEPCs in the TEWAK + Fn14 siRNA group and the TWEAK + LY groups were significantly decreased. The expression of p-Akt in the TWEAK group was significantly higher than that in the control group，while the expression of p-Akt in the TWEAK + Fn14 siRNA group and the TWEAK + LY group was significantly lower than that in the TWEAK group. Conclusion：TWEAK can regulate the angiogenesis of hEPCs and its angiogenesis may be restricted by Fn14-PI3K-Akt signaling pathway.