Background: Several studies indicate that organ failure is the leading cause of death in the postoperative phase after major surgery. An excessive inflammatory response followed by a dramatic depression of cell-mediated immunity after major surgery appears to be responsible for the increased susceptibility to subsequent sepsis. In view of this, most of the scientific and medical research has been directed towards measuring the progression and interrelationship of mediators after major surgery. Furthermore, the effect of those mediators on cell-mediated immune responses has been studied. Objective: This article focuses on the effect of surgical injury and blood loss on cell-mediated immune responses in experimental studies utilizing models of trauma and hemorrhagic shock. The findings from those experimental studies will also be correlated with data from surgical patients. Results: Recently, a gender-dimorphic immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis has been found. Androgens have been shown to be responsible for the immunosuppression after trauma-hemorrhage in males. In contrast, female sex steroids exhibit immunoprotective properties after trauma and severe blood loss. Conclusion: In view of these findings, clinically relevant therapeutic strategies have been developed using the testosterone receptor blocker flutamide and/or estrogen or agents with estrogenic effects, i.e., dehydroepiandrosterone, which might yield safe and useful therapeutic approaches for the treatment of immune depression in surgical patients. © Springer-Verlag 2005.