Background: Bone loss is a well-documented phenomenon occurring in humans both in short- and long-term spaceflights. Revealing data on the role of erythropoietin (EPO) in bone formation has led some to suggest that EPO treatment could also play a role in protecting bone against microgravity-induced bone loss. The aim of the present study was to investigate the effects of EPO administration on densitometric changes of femur of rat in a Microgravity Simulation Model (MSM). Materials and methods: Twelve rats were divided into two groups: the tail-suspended control (TSC), and the tail-suspended group treated with rhEpo (TSE) (300 U/kg every 48 hours). The experiment lasted for 3 weeks. The animals were sacrificed, the right femur of each rat was removed, and bone mineral density was measured for each animal. Results: Bone mineral density of whole femur in TSE group was significantly higher than TSC group (0.160±0.003 vs. 0.144±0.006, p=0.002). Conclusion: According to the results of this study, Erythropoietin administration might have protective effects against microgravity-induced mineral loss in a rat MSM.