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Glutamine (Gln)–supplemented total parenteral nutrition (TPN) improves clinical outcome after planned surgery, but the benefits of Gln-TPN for critically ill (intensive care unit; ICU) patients are still debated.Prospective, double-blind, controlled, randomized trial.ICUs in 16 hospitals in France.One-hundred fourteen ICU patients admitted for multiple trauma (38), complicated surgery (65), or pancreatitis (11).Patients were randomized to receive isocaloric isonitrogenous TPN via a central venous catheter providing 37.5 kcal and 1.5 g amino acids·kg−1·day−1 supplemented with either L-alanyl-L-glutamine dipeptide (0.5 g·kg−1·day−1; Ala-Gln group, n = 58) or L-alanine + L-proline (control group, n = 56) over at least 5 days.Complicated clinical outcome was defined a priori by the occurrence of infectious complications (according to the criteria of the Centers for Disease Control and Prevention), wound complication, or death. The two groups were compared by chi-square test on an intention-to-treat basis. The two groups did not differ at inclusion for type and severity of injury (mean simplified acute physiology score II, 30 vs. 30.5; mean injury severity score, 44.9 vs. 42.3). Similar volumes of TPN were administered in both groups. Ala-Gln-supplemented TPN was associated with a lower incidence of complicated outcome (41% vs. 61%; p < .05), which was mainly due to a reduced infection rate per patient (mean, 0.45 vs. 0.71; p < .05) and incidence of pneumonia (10 vs. 19; p < .05). Early death rate during treatment and 6-month survival were not different. Hyperglycemia was less frequent (20 vs. 30 patients; p < .05) and there were fewer insulin-requiring patients (14 vs. 22; p < .05) in the Ala-Gln group.TPN supplemented with Ala-Gln dipeptide in ICU patients is associated with a reduced rate of infectious complications and better metabolic tolerance.