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Glutamine is recognized as a conditionally indispensable amino acid. The purpose of the current study was to investigate whether supplemental l-alanyl-l-glutamine to parenteral nutrition can alter clinical outcome in intensive care unit patients.Prospective, open, randomized trial.Postoperative intensive care unit of a university hospital.Male and female critically ill patients with indications for parenteral nutrition and an expected stay on intensive care unit for ≥5 days.Patients were randomized to receive either standard parenteral nutrition or supplemented parenteral nutrition with l-alanyl-l-glutamine (0.3 g·kg−1·body weight−1 [bw] per day). Total amount of amino acids comprised 1.5 g·kg−1·bw−1 per day. Caloric support was managed by metabolic variables (glucose and triglyceride plasma values). Target values for energy supply were 3 g·kg−1·bw−1 carbohydrates and 1 g·kg−1·bw−1 fat per day.Medical treatment, nutritional therapy, vital variables, and biochemical data were recorded. Clinical outcome was measured by average length of stay in the intensive care unit and hospital and the mortality in the intensive care unit and within 30 days and 6 months. A total of 144 patients were randomized; 95 patients were treated for ≥5 days and 68 patients for ≥9 days under standardized conditions. In the treatment group, plasma glutamine concentrations significantly increased within 6–9 days. Six-month survival was significantly improved for patients treated for ≥9 days (66.7% [glutamine supplemented] vs. 40% [control]).Study results support the hypothesis that replacement of glutamine deficiency may correct the excess mortality in intensive care unit patients caused by inadequate parenteral nutrition.