Several studies indicate that organ failure is the leading cause of death in surgical patients. An excessive inflammatory response followed by a dramatic paralysis of cell-mediated immunity following 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 inter-relationship of mediators following major surgery. Furthermore, the effect of those mediators on cell-mediated immune responses has been studied. This article will focus on the effect of blood loss and surgical injury on cell-mediated immune responses in experimental studies utilizing models of trauma and hemorrhagic shock, which have defined effects on the immunoinflammatory response. Subsequently these findings will be correlated with data generated from surgical patients. The results of these studies may generate new approaches for the treatment of immunodepression following major surgery, thus reducing the susceptibility to infection and increasing the survival rate of the critical ill surgical patient.