Background. Ischemia/reperfusion injury (I/R injury) to the liver can occur in low-flow states associated with trauma and shock and surgical procedures such as liver transplantation. Recent studies have shown that the administration of the female sex hormone 17-β-estradiol after trauma-hemorrhage in animals restores depressed cardiac, hepatocellular, and immune functions. In this study we evaluated the effects of 17-β-estradiol on I/R injury to the liver. Methods. The medial lobe of the liver in normal male C57BL/6 mice was clamped at its base for 90 minutes. 17-Beta-estradiol was given 1 hour before I/R injury at 40 and 4000 μg/kg intraperitoneally. Biochemical analysis was performed, and liver biopsy specimens were obtained at 24 hours. Results. A dose-dependent reduction in aspartate aminotransferase level was observed in animals (n = 8) given estradiol (243 ± 23 IU/L) compared with saline-treated animals (902 ± 42 IU/L, P < .001). The majority (90%) of the cytoprotective effect of estradiol was reverted by ICI 182, 780 (a potent estrogen receptor antagonist). A significant increase in serum nitric oxide (NO) level was observed in animals given estradiol compared with controls; the effect was reversed by ICI 182, 780 and N-nitro-L-arginine-methyl ester (an inhibitor of NO synthesis). A reduction in serum tumor necrosis factor-α was observed after injury in animals given estradiol compared with controls (30.2 ± 11.1 vs 75.8 ± 17.2 pg/mL, P < . 001). Estradiol treatment significantly reduced liver necrosis, disintegration of hepatic cords, and neutrophil infiltration in an estrogen receptor-dependent manner. Conclusions. Estradiol administration significantly reduced injury after I/R to the liver, an effect that is mainly receptor-mediated and is associated with increased serum NO, decreased TNF-α, and decreased number of neutrophils in liver biopsy specimens. Estrogen therapy may be important in clinical conditions associated with I/R injury to the liver.