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Studies have failed to consistently demonstrate improved survival in intensive care unit (ICU) patients receiving immune-modulating nutrient-enhanced enteral feeds when compared with standard enteral feeds. The objective was to study in a prospective fashion the effects of adding glutamine to standard or immune-modulated (supplemented with omega-3 fatty acids, β-carotene, and amino acids such as glutamine and arginine) tube feeds.Prospective, unblinded study using sequential allocation.A university surgical trauma ICU.All surgical and trauma patients admitted to the surgical trauma ICU at a university hospital over a 3-yr period who were to receive enteral feeds (n = 185).Sequential assignment to three isocaloric, isonitrogenous diets was performed as follows: standard 1-kcal/mL feeds with added protein (group 1), standard feeds with the addition of 20–40 g/day (0.6 g/kg/day) glutamine (group 2), or an immune-modulated formula with similar addition of glutamine (group 3). The goal for all patients was 25–30 kcal/kg/day and 2 g/kg/day protein.Patients were followed until discharge from the hospital. The primary end point was in-hospital mortality, and multiple secondary end points were recorded. In-hospital mortality for group 1 was 6.3% (four of 64) vs. 16.9% (ten of 59, p = .09) for group 2 and 16.1% (ten of 62, p = .09) for group 3. After controlling for age and severity of illness, the difference in mortality between patients receiving standard tube feeds and all patients receiving glutamine was not significant (p ≤ .11). There were no statistically significant differences between the groups for secondary end points.The addition of glutamine to standard enteral feeds or to an immunomodulatory formula did not improve outcomes. These findings suggest that enteral glutamine should not be routinely administered to patients with surgical critical illness.