It is estimated that 100 million individuals suffer from severe limb ischemia worldwide. Here, we report a novel therapy for severe limb ischemia by transplanting autologous peripheral blood stem cells (PBSCs). Thirty patients with different limb ischemia were enrolled and randomized to either stem cell injection or standard therapy in the study. The patients in the transplant group received intramuscular injections of autologous PBSCs collected after G-CSF-induced stem cell mobilization. Lower limb pain, ulcer repair and wound healing and blood perfusion were improved in the cell treated group. All cell treated patients achieved successful limb salvage. Analysis by digital subtraction angiography demonstrated the formation of new collateral vessels in the ischemic limbs of transplanted patients after cell injection. In contrast, no significant improvement was observed in the control patients. These results provide pilot evidence indicating that transplantation of autologous PBSCs is a simple and effective therapeutic angiogenesis for limb ischemia. To determine the mechanism of action, several animal experiments were performed by transplanting human PBSCs via tail vein into nude mice. It was found that the transplanted cells survived and incorporated into capillary networks in murine ischemic limb. Laser Doppler Perfusion Image (LDPI) and histological analysis revealed that the transplantation of human PBSCs augmented blood flow and neovascularization in the ischemic hindlimb, ameliorated necrosis and improved limb salvage. Our results demonstrate that PBSCs are excellent cell population capable of augmenting neovascularization.