Background COMP-Angiopoietin-1 (Ang1), a newly designed Ang1 variant showed independent efficacy of angiogenesis without VEGF, in contrary to natural recombinant Ang1. Also, recent studies indicated that Ang1 directly promotes cardiac and skeletal myocyte survival through integrins in vitro. We hypothesized that COMP-Ang1 could effectively salvages ischemic limb by dual action, Methods and Results In the local group, COMP-Ang1 was injected into the mice adductor after ischemia was induced by surgical excision of femoral artery. COMP-Ang1 was administered via tail vein for 7 days in the systemic group. Control group received saline injection. Gross complete limb salvage rate was 60%, 50% and 20% in systemic, local COMP-Ang1 group and the control group. Blood flow was assessed over the course of 2weeks postoperatively and showed the stastically significant improvement in COMP-Ang1 groups (local and systemic) than in the control group (p<0.05). Capillary densities at postoperative day 14 also were higher in COMP-Ang1 groups (p<0.05). At postoperative day 3 immunofluorescent staining showed increased western blot analysis revealed that 棺2-integrin, ICAM-1 and Tek (mouse Tie 2-receptor) expression in COMP-Ang1 groups. Interestingly, local injection group showed massive infiltration of inflammatory cells and partial necrosis with regeneration of skletal myocyte in gastrocnemius, but not in adductor. In contrast, systemic injection group had scanty inflammation and intact myocytes and control group showed necrosis and inflammation in both levels. Conclusion COMP-Ang1 enhanced angiogenesis and survival of skeletal myocyte in the ischemic tissue. Increased expression of Tek sensitizes Tek-mediated endothelial survival and angiogenesis. COMP1-棺2-integrin interaction enhances survival of skeletal myocyte and increased expression of 棺2-integrin and ICAM-1 may facilitate the homing of endothelial progenitor cells. Different action according to the method of administration suggests that there is different mechanism of limb salvage between two modalities and further studies are needed.