Current trials of immune-enhancing diets suggest several beneficial clinical effects. These products are associated with a reduction in infectious risk, ventilator days, ICU and hospital stay. However, methodological weaknesses limit the inferences we can make from these studies. Furthermore, improvements in outcomes were largely seen in surgical patients and in patients who tolerated critical amounts of formula. We propose that the beneficial findings cannot easily be extrapolated to other patient populations since there is suggestion from clinical trials that the sickest patients, especially those with severest appearances of sepsis, shock and organ failure may not benefit or may even be harmed. In these conditions we hypothesize that systemic inflammation might be undesirably intensified by immune-enhancing nutrients like arginine in critically ill patients. In this paper, we review the purported effects of arginine on the immune system and organ function to understand the scientific rationale for its inclusion into enteral feeding products. We conclude that patients with the most severe appearances of the systemic inflammatory response syndrome should not receive immune-enhancing substrates which may aggravate systemic inflammation and worsen clinical outcomes.