Background: Hepatic ischemia/reperfusion (I/R) injury continued to be a significant clinical problem. The aim of this study was to examine whether the protective effects of 17-estradiol (E2) on hepatic ischemia/reperfusion (I/R) injury was associated with the downregulation of the angiotensin 11 (Ang II)/AT1R pathway. Methods: Forty male Sprague Dawley rats were randomized into five groups: Sham operation, ischemia/reperfusion (UR), I/R + E2, I/R + E2+estrogen receptor antagonist ICI 182,780 (ICI), and I/R + E2+ Ang II subtype I receptor (AT1R) antagonist losartan (LOS) groups. A model of total hepatic I/R was established by portal pedicle clamping for 60 min followed by reperfusion. At onset of ischemia, rats were treated with vehicle, E2, or LOS. ICI was given 30 min before E2 administration. At 24 h after reperfusion, blood samples and liver tissues were collected and subjected to histological examination, biochemical assays, and Western blot assays. Results: Compared with I/R group, the degree of hepatocyte damage, serum ALT and TNF-alpha levels, hepatic MDA level and MPO activity were decreased in I/R + E2 group (all p < 0.05). Moreover, the serum and liver Ang II levels and hepatic AT1R protein level in I/R + E2 group were also significantly reduced compared with I/R group (all p < 0.05). However, the protective effect of E2 could be abolished by ICI administration. In contrast, administration of LOS conferred similar, but not as effective as E2, protective effects on hepatic I/R injury, without affecting Ang II and AT1R levels. Conclusions: The salutary effects of E2 on hepatic I/R injury are mediated in part by downregulating the Ang II/AT1R pathway. (C) 2018 Elsevier Inc. All rights reserved.