Several nutrients have been shown to influence immunologic and inflammatory responses in humans. Whether these effects translate into an improvement in clinical outcomes in critically ill patients remains unclear. To examine the relationship between enteral nutrition supplemented with immune-enhancing nutrients and infectious complications and mortality rates in critically ill patients. The databases of MEDLINE, EMBASE, Biosis, and CINAHL were searched for articles published from 1990 to 2000. Additional data sources included the Cochrane Controlled Trials Register from 1990 to 2000, personal files, abstract proceedings, and relevant reference lists of articles identified by database review. A total of 326 titles, abstracts, and articles were reviewed. Primary studies were included if they were randomized trials of critically ill or surgical patients that evaluated the effect of enteral nutrition supplemented with some combination of arginine, glutamine, nucleotides, and omega-3 fatty acids on infectious complication and mortality rates compared with standard enteral nutrition, and included clinically important outcomes, such as mortality. Methodological quality of individual studies was scored and necessary data were abstracted in duplicate and independently. Twenty-two randomized trials with a total of 2419 patients compared the use of immunonutrition with standard enteral nutrition in surgical and critically ill patients. With respect to mortality, immunonutrition was associated with a pooled risk ratio (RR) of 1.10 (95% confidence interval [CI], 0.93-1.31). Immunonutrition was associated with lower infectious complications (RR, 0.66; 95% CI, 0.54-0.80). Since there was significant heterogeneity across studies, we examined several a priori subgroup analyses. We found that studies using commercial formulas with high arginine content were associated with a significant reduction in infectious complications and a trend toward a lower mortality rate compared with other immune-enhancing diets. Studies of surgical patients were associated with a significant reduction in infectious complication rates compared with studies of critically ill patients. In studies of critically ill patients, studies with a high-quality score were associated with increased mortality and a significant reduction in infectious complication rates compared with studies with a low-quality score. Immunonutrition may decrease infectious complication rates but it is not associated with an overall mortality advantage. However, the treatment effect varies depending on the intervention, the patient population, and the methodological quality of the study.