Commercial enteral nutritional formulas for enhancement of the immune system are widely used in critical care. Immunonutrition with arginine can enhance inflammatory and immunologic responses in animal models and in humans. Although clinical improvements in surgical patients have been reported, benefits in critically ill patients with systemic inflammatory response syndrome, sepsis, or organ failure are less clear. Recent meta-analyses on the use of immunonutrition with arginine in critically ill and surgical patients revealed methodological weaknesses in most published studies. Specifically, a meta-analysis indicated that critically ill patients with preexisting severe sepsis may have an increased mortality rate when fed an immunonutritional enteral formula that contains arginine. These findings brought about confusion and controversy over the use of immunonutritional formulas in subsets of critically ill patients. A review of the literature on the function of arginine, its effect on the immune system, its roles in immunonutrition and in the clinical outcomes of critically ill patients, and the implications for nursing practice indicated that the benefits of immunonutrition with arginine in critically ill patients are unproven and warrant further study. Until more information is available, nutritional support should focus primarily on preventing nutritional deficiencies rather than on immunomodulation.