© 2015 by the Shock Society. Casodex (bicalutamide), an androgen receptor antagonist, is used for the treatment of prostate cancer. Recent evidences show that Akt signaling pathway exerts organ-protective effects after injury. The aim of this study was to investigate whether Akt plays any role in the casodex-mediated attenuation of hepatic injury after trauma-hemorrhagic shock. Male Sprague-Dawley rats underwent trauma hemorrhage (mean blood pressure kept at approximately 35Y40 mm Hg for 90 min), followed by fluid resuscitation. During resuscitation, a single dose of casodex (5 mg/kg, intravenous) with and without a phosphatidylinositol 3-kinase inhibitor wortmannin (1 mg/kg, intravenous), wortmannin or vehicle was administered. Plasma aspartate aminotransferase and alanine aminotransferase levels and various hepatic parameters were measured at 24 h after resuscitation. One-way analysis of variance and the Tukey test were used for statistical analysis. These results showed that trauma hemorrhage increased hepatic myeloperoxidase activity, interleukin 6 and intercellular adhesion molecule 1 levels, and plasma aspartate aminotransferase and alanine aminotransferase concentrations. In the trauma hemorrhage rats treated with casodex, these parameters were significantly improved. Casodex treatment also increased hepatic phospho-Akt expression compared with vehicle-treated trauma hemorrhaged rats. Coadministration of wortmannin with casodex abolished the casodex-induced advantageous effects on the aforementioned parameters and hepatic injury. Our results suggest that the protective effect of casodex administration on attenuation of hepatic injury after trauma hemorrhage, which is, at least in part, through Akt-dependent pathway.