Although studies have shown that administration of testosterone receptor antagonist, flutamide, following trauma-hemorrhage improves hepatic, cardiovascular and immune functions, the precise cellular/molecular mechanisms responsible for producing these salutary effects remain largely unknown. To study this, male C3H/HeN mice were subjected to a midline laparotomy and hemorrhagic shock (35 ± 5 mm Hg for approximately 90 min), followed by resuscitation with Ringer lactate. Flutamide (25 mg/kg) or vehicle was administered subcutaneously at the onset of resuscitation and animals were sacrificed 2 hrs thereafter. Hepatic injury was assessed by plasma -GST concentration, liver myeloperoxidase (MPO) activity and nitrotyrosine formation. Hepatic malondialdehyde (MDA) and 4-hydroxyalkenals (HAE) (lipid peroxidation indicators), cellular DNA fragmentation and the expression of iNOS and HIF-1 were also evaluated. Cytokines (TNF-, IL-6) and chemokines (keratinocyte-derived chemokine-KC and MCP-1) levels were determined by cytometric bead array. The results indicate that flutamide administration after trauma-hemorrhage reduced liver injury which was associated with decreased levels of -GST, MPO activity, nitrotyrosine formation, lipid peroxidation and cytokines/chemokines (systemic, liver tissue and intracellular cytokines/chemokines). Cellular apoptosis, hepatocyte HIF-1 and iNOS expression were also decreased under such conditions. Thus, administration of flutamide following trauma-hemorrhage protects against liver injury via reduced inflammation, cellular oxidative stress and apoptosis.