backgrounds: Circulating progenitor cells (CPC) enhanced neovascularization in experimental ischemic disease in contrast to myelomonocytic cells although both cells shared surface markers and some angiogenic factors. This study was performed to reveal the differential mechanism of CPC in neovascularization compared to myelomonocytic cells Methods: We transduced CPC and CD14+-derived macrophages (MP) with a suicidal gene, viral thymidine kinase to deplete the cells in vivo by ganciclovir (GCV) administration. We induced critical hindlimb ischemia in nude mice and then transplanted one type of the cells or PBS into the mice. We divided each group into two subgroups and injected either GCV or PBS for five days from 7 days after operation and obtained laser Doppler perfusion image weekly. Results: At 2 weeks, CPC showed significantly enhanced perfusion recovery in contrast to MP. When we depleted the cells from day 7, we found that the improved perfusion was significantly abrogated in CPC group. Although MP persisted in vivo at later phase, they resulted in morphologically unstable and functionally invalid neovascularization. Cytokine array and in vivo Matrigel plug model revealed that macrophages secreted different cytokines and induced unhealthy vessels compared to CPC. Finally, CPC enhanced migration of mesenchymal cells which is important for vascular stabilization. In conclusion, CPC persisted long in the ischemic tissue, enhanced neovascularization by balanced cytokines and stabilized new vessels by recruiting mesenchymal cells. CPC have complex long-term angiogenic potential which cannot be substituted by differentiated cells.