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Background: In severe acute pancreatitis (AP), intravenous glutamine has been shown to reduce the rate of complications, hospital stay, and mortality. In the present randomized trial, we aimed to evaluate the effect of enteral glutamine supplementation on clinical outcomes, gut permeability, systemic inflammation, oxidative stress, and plasma glutamine levels in patients with severe and predicted severe AP., Methods: Patients with AP admitted within 72 h of onset of symptoms were included. The primary outcome measure was development of infected pancreatic and peri-pancreatic necrosis and in-hospital mortality. High-sensitivity C-reactive protein (HS-CRP) and interleukin-6 (IL-6) were evaluated as markers of inflammation; plasma thiobarbituric acid reactive substances (TBARS) and activities of serum superoxide dismutase and glutathione peroxidase were determined to evaluate oxidative stress; serum polyethylene glycol (PEG) was tested for intestinal permeability; subjective global assessment (SGA) was used for nutritional assessment, and an improvement in organ function was measured by the Modified Marshall score. Intention-to-treat analysis was used. A p-value of < 0.05 was considered statistically significant., Results: After power calculation, we enrolled 18 patients in the glutamine and 22 in the control arm. There was no significant improvement in the development of infected necrosis and in-hospital mortality between the groups. Improvement in Modified Marshall score was observed in a higher proportion of patients receiving glutamine (15 [83.3%] vs. 12 [54.5%]; p = 0.05). Plasma glutamine levels improved more in glutamine-treated group (432.72 ± 307.83 vs. 618.06 ± 543.29 μM/L; p = 0.004), while it was lower in controls (576.90 ± 477.97 vs. 528.20 ± 410.45 μM/L; p = 0.003). PEG level was lower after glutamine supplementation (39.91 ± 11.97 vs. 32.30 ± 7.39 ng/mL; p = 0.02). Statistically significant reduction in IL-6 concentration was observed in the glutamine group at the end of treatment (87.44 ± 7.1 vs. 63.42 ± 33.7 μM/L; p = 0.02)., Conclusions: Despite absence of improvement in infected necrosis and in-hospital mortality, enteral glutamine supplementation showed improvement in gut permeability, oxidative stress, and a trend towards improvement in organ function as depicted by improvement in the Modified Marshall score., Trial Registration: NCT01503320.