Beyond its role in the regulation of red blood cell proliferation, the glycoprotein erythropoietin (EPO) has been shown to promote cell regeneration and angiogenesis in a variety of different tissues. In addition, EPO has been indicated to share significant functional and structural homologies with the vascular endothelial growth factor (VEGF), a cytokine essential in the process of fracture healing. However, there is complete lack of information on the action of EPO in bone repair and fracture healing. Therefore, we investigated the effect of EPO treatment on bone healing in a murine closed femur fracture model using radiological, histomorphometric, immunohistochemical, biomechanical and protein biochemical analysis. Thirty-six SKH1-hr mice were treated with daily i.p. injections of 5000 U/kg EPO from day 1 before fracture until day 4 after fracture. Controls received equivalent amounts of the vehicle. After 2 weeks of fracture healing, we could demonstrate expression of the EPO-receptor (EPOR) in terminally differentiating chondrocytes within the callus. At this time point EPO-treated animals showed a higher torsional stiffness (biomechanical analysis: 39.6 ± 19.4% of the contralateral unfractured femur) and an increased callus density (X-ray analysis (callus density / spongiosa density): 110.5 ± 7.1%) when compared to vehicle-treated controls (14.3 ± 8.2% and 105.9 ± 6.6%; p < 0.05). Accordingly, the histomorphometric examination revealed an increased fraction of mineralized bone and osteoid (33.0 ± 3.0% versus 28.5 ± 3.6%; p < 0.05). Of interest, this early effect of the initial 6-day EPO treatment had vanished at 5 weeks after fracture. We conclude that EPO–EPOR signaling is involved in the process of early endochondral ossification, enhancing the transition of soft callus to hard callus.