Background: Renal ischemia–reperfusion (RIR) is an important etiopathological mechanism of acute renal failure (ARF). Erythropoietin (EPO) has been candidate as a nephroprotectant agent. However, its nephroprotective effect when it is accompanied with estrogen has not been studied in female. Methods: Fifty-six female rats were divided into seven groups. Each formed of 8 rats. Group I: control group. Group II: Female rats exposed to RIR (named RIR group).Group III: Female rats exposed to RIR and pretreated with EPO (named RIR + EPO group). Group IV: ovariectomized rats exposed to RIR (named OVR + RIR group). Group V: ovariectomized rats received estrogen (E) then exposed to RIR (named OVR + RIR + E group). Group VI: ovariectomized rats received EPO before RIR (named OVR + RIR + EPO group). Group VII: ovariectomized rats received E then received EPO before RIR (named OVR +RIR +E + EPO group).Serum creatinine, blood urea nitrogen (BUN) and renal blood flow (RBF) were measured. Tumor necrosis factor-a(TNF-a), Myeloperoxidase activity (MPO), nitric oxide (NO), endothelin-1(ET-1) and EPO levels were assessed in the renal tissue. Histopathology was assessed to detect renal damage score. Results: RIR significantly increased the serum levels of creatinine and BUN with decrease in RBF. In addition it significantly increased TNF-a, MPO and endothelin-1 levels with decrease in NO and EPO levels in renal tissue. However, these parameters significantly reversed by EPO except RBF. Combination of E and EPO leads to significant decrease in the protective effect of EPO. Conclusion: It seems that EPO could protect the kidney against RIR, while this protective effect was decreased when E was supplemented.