Abstract: Objective The long-term use of glucocorticoids can lead to femoral head necrosis with high disability rate. This research is designed to explore possible methods to prevent femoral head necrosis and discuss its mechanism by using rat model with simultaneous injection of erythropoietin (EPO). Methods SD Rats were divided into 3 groups according to random number table, half male and half female. Model group:intramuscular injection of methyl prednisolone 20 mg/kg, b.i.w, for six weeks; EPO group:intraperitoneal injection of EPO, b.w 500 U/kg, q.d; Negative control group:injection of normal saline. Twelve weeks after the treatment, the femoral neck tissues were prepared for HE staining (histological examination), immunohistochemistry (PECAM-1) and Western blot (PCNA and VEGF). Main statistical methods were one-way ANOVA (under software SPSS 19.0). Results Histology:compared with experimental group, the model group had shown the sparse, fracture, irregular shape accompanied by nucleus shrinkage, dissolved and disappeared bone trabeculae. Immunohistochemical results:Negative control group was with the highest expression of PECAM-1, followed by EPO group and model group(male rats one-way ANOVA:F=45.776, female F=23.850, P<0.01. Dunnett T3 method was conducted for comparison between groups). Western Blot results:VEGF and PCNA expression in EPO group was higher as compared with the model group, there was no statistical significance when compared with Negative control group (one-way ANOVA PCNA:F=6.857, VEGF:F=7.025, P<0.05, LSD m Method was conducted for comparison between groups). Conclusion Synchronal injection of EPO can prevent steroid-induced necrosis of the femoral head.