Both malnutrition and the physical injury related to trauma and surgery increase the expression of T-helper 2 (Th2) lymphocytes which cause impaired cell mediated immunity. Activation of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system with the release of cortisol and catecholamines drive the development of Th2 cells. Th2 cytokines result in the accumulation of arginase-1 expressing myeloid-derived suppressor cells in lymphoid tissue. The myeloid-derived suppressor cells cause an arginine deficient state resulting in impaired lymphocyte function. Prostaglandin-E2 released following trauma plays a synergetic role with cortisol and catecholamines in driving these pathways. There is now increasing evidence that immunomodulating enteral formulas supplemented with arginine and omega-3 fatty acids can reverse many of the immune mediated changes and decrease the number of adverse outcomes after major surgery and trauma. These immunomodulating enteral formulas should be strongly considered in surgical patients undergoing major surgery and following severe trauma.