Trauma-hemorrhage initiates inflammation in males that leads to a systemic inflammatory response syndrome (SIRS) and immunosuppression, which in turn may develop into multiple organ dysfunction syndrome (MODS). In contrast, females, in the proestrus state (which is associated with elevated estrogen levels), do not show immune depression following trauma-hemorrhage. Studies in experimental models have demonstrated that the underlying basis for this gender-dimorphic immune response following trauma-hemorrhage is due to the marked effects of sex hormones. Sex hormones influence the onset and severity of immune-mediated pathophysiological conditions primarily by modulating immune cell function. Nonetheless, despite extensive studies, the mechanisms of sex hormone action are yet to be precisely defined. Earlier studies had suggested that the sex hormone-mediated modulation of immune activity was primarily via the thymus. In recent years, however, it has become apparent that sex hormones can also influence the immune system by acting on several nonthymic targets such as monocytes, macrophages, lymphoid cells, endothelial cells and the central nervous system. However, more research is needed to define the mechanism responsible for gender-specific immune response to trauma-hemorrhage. These studies will likely contribute to the therapeutic modalities that include manipulation of sex hormones, and/or their receptor agonist/antagonists in the treatment of traumatized patients. © 2003 Elsevier B.V.