A chimeric form of Ang1, termed COMP-Ang1 (cartilage oligomeric matrix protein-Ang1) was recently reported to induce the long-lasting vascular enlargement and increase the tracheal blood flow. However, the usefulness of COMP-Ang1 in the treatment of ischemic limb diseases has not been tested. In the present study, we investigated whether COMP-Ang1 can enhance blood flow in a murine model of hindlimb ischemia. After inducing unilateral hindlimb ischemia in Balb/c mice, the adenoviral vectors encoding COMP-Ang1, Ang1, or LacZ was injected into the adductor muscle of the ischemic leg followed by measurement of the blood flow recovery using laser Doppler imaging system at 3, 7, 14, and 21 days. The phosphate-buffered saline served as a vehicle control. In contrast to the slow revascularization in PBS-, Ad-LacZ-, and Ad-Ang1-treated groups, a rapid increase in tissue perfusion was observed in the Ad-COMP-Ang1 group, where its blood flow recovery was significantly higher at day 7 (p < 0.05 versus PBS or Ad-LacZ). Consistent with this finding, the frequency of limb necrosis due to the vascular insufficiency was significantly decreased in Ad-COMP-Ang1 and Ad-Ang1 groups, compared with the control (PBS and Ad-LacZ) groups. Moreover, the serum levels of muscle damage markers, such as creatine kinase (CK) and lactate dehydrogenase (LDH), were reduced in both Ad-COMP-Ang1 and Ad-Ang1 groups. These observations suggest that COMP-Ang1 might be useful in enhancing tissue perfusion in ischemic leg. Our study has important ramifications for the treatment of peripheral arterial occlusive diseases. Key Words: COMP-Ang1, ischemia, blood flow, perfusion, CK, LDH