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To examine the relationship between glutamine supplementation and hospital length of stay, complication rates, and mortality in patients undergoing surgery and experiencing critical illness.Computerized search of electronic databases and search of personal files, abstract proceedings, relevant journals, and review of reference lists.We reviewed 550 titles, abstracts, and articles. Primary studies were included if they were randomized trials of critically ill or surgical patients that evaluated the effect of glutamine vs. standard care on clinical outcomes.We abstracted relevant data on the methodology and outcomes of primary studies in duplicate, independently.There were 14 randomized trials comparing the use of glutamine supplementation in surgical and critically ill patients. When the results of these trials were aggregated, with respect to mortality, glutamine supplementation was associated with a risk ratio (RR) of 0.78 (95% confidence interval [CI], 0.58–1.04). Glutamine supplementation was also associated with a lower rate of infectious complications (RR, 0.81; 95% CI, 0.64–1.00) and a shorter hospital stay (−2.6 days; 95% CI, −4.5 to −0.7). We examined several a priori–specified subgroups. Although there were no statistically significant subgroup differences detected, there were some important trends. With respect to mortality, the treatment benefit was observed in studies of parenteral glutamine (RR, 0.71; 95% CI, 0.51–0.99) and high-dose glutamine (RR, 0.73; 95% CI, 0.53–1.00) compared with studies of enteral glutamine (RR, 1.08; 95% CI, 0.57–2.01) and low-dose glutamine (RR, 1.02; 95% CI, 0.52–2.00). With respect to hospital length of stay, all of the treatment benefit was observed in surgical patients (−3.5 days; 95% CI, −5.3 to −1.7) compared with critically ill patients (0.9 days; 95% CI, −4.9 to 6.8).In surgical patients, glutamine supplementation may be associated with a reduction in infectious complication rates and shorter hospital stay without any adverse effect on mortality. In critically ill patients, glutamine supplementation may be associated with a reduction in complication and mortality rates. The greatest benefit was observed in patients receiving high-dose, parenteral glutamine.