Objective  To investigate the mechanism of alleviating renal ischemia/reperfusion injury by pretreatment with sevoflurane and the correlation with the expression of hypoxia-inducible factor-2α (HIF-2α). Methods  Wild type mice and HIF-2α knockout (HIF-2α-/-) mice were randomly divided into sham operation group (control group), renal ischemia/reperfusion group (I/R group), and sevoflurane pretreatment+renal ischemia/reperfusion group (Sev+I/R group). Levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were detected in blood samples after operation. Renal tissues were harvested to detect the pathological changes and the protein expression of HIF-2α in renal tissues was detected by Western blotting. Results  Compared with the control group, BUN and SCr levels of wild type mice and HIF-2α-/- mice of I/R group were significantly higher (P<0.001). For Sev+I/R group, BUN and SCr levels of wild type mice were significantly lower than those of HIF-2α-/- mice (P<0.001). Results of pathological examination indicated that all mice of I/R group showed pathological characteristics of severe acute renal injury. However, for Sev+I/R group of wild type mice, only mild pathological injury was found and the expression of HIF-2α  was significantly higher than that of control group and I/R group. But for Sev+I/R group of HIF-2α-/- mice, the pathological injury of kidneys was not alleviated compared with that of I/R group. Conclusion  Sevoflurane pretreatment can protect the renal function for renal ischemia/reperfusion injury, which may be relevant to up-regulating the expression of HIF-2α in renal tissues.