The objective of this study was to evaluate the effects of local endothelial progenitor cell (EPC) therapy on bone regeneration in a rat model. A segmental bone defect (5 mm) was created in the femur and fixed with a mini-plate. There were two groups: EPC-treated (N ¼ 28) and control (N ¼ 28). Seven animals were sacrificed from each group at 1, 2, 3, and 10 weeks postoperatively. Healing of the defect was evaluated with radiographic, histological, and quantitative micro-computed tomography (micro-CT) scans. Radiographically, mean scores of the EPC and control groups were, respectively, 1.16-0.61 (p < 0.05) at 1 week, 2.53-1.54 (p < 0.05) at 2 weeks, and 4.58-2.35 at 3 weeks (p < 0.05). At 10 weeks, all the animals in the EPC-treated group had complete union (7/7), but in the control group none achieved union (0/7). Histological evaluation revealed that specimens from EPC-treated animals had abundant new bone and vessel formation compared to that in controls. Micro-CT assessment of the samples from the animals sacrificed at 10 weeks (N ¼ 14) showed significantly improved parameters of bone volume (36.58-10.57, p ¼ 0.000), bone volume density (0.26-0.17, p ¼ 0.000), model index À2.22-2.79, p ¼ 0.000), trabecular number (1.28-0.91, p ¼ 0.063), trabecular thickness (0.21-0.15, p ¼ 0.001), trabecular spacing (0.63-1.07, p ¼ 0.022), bone surface (353.75-152.08, p ¼ 0.000), and bone surface to bone volume ratio (9.54-14.24, p ¼ 0.004) for the EPC group compared to control, respectively. In conclusion, local EPC therapy significantly enhanced bone regeneration in a segmental defect model in rat femur diaphysis. ß