OBJECTIVE The aim of this study is to evaluate the effect of oral glutamine (GL) supplementation on gut permeability and endotoxemia (surrogate end point) in patients with severe acute pancreatitis. METHODS In a randomized controlled trial, patients were randomized to be given placebo or GL for 7 days. The primary outcome measures include the effect on gut permeability (assessed by lactulose/mannitol excretion in urine and endotoxemia assessed by endotoxin core antibodies type IgG and IgM (EndoCab IgG and IgM). The secondary outcome measures include infectious complications, mortality, total hospital/intensive care unit stay, C-reactive protein, and prealbumin levels. RESULTS Patients were assigned to GL (n = 41) and placebo (n = 39) groups. There was no change in gut permeability after the intervention. However, the EndoCab IgM levels increased significantly (33 [4, 175] to 40 [8, 350] GMU/mL; P = 0.0164) and the C-reactive protein levels decreased significantly (133 [1, 287] to 88 [1, 267] ng/mL; P = 0.0236) in the GL group. No difference was observed in infectious complication, prealbumin value, hospital/intensive care unit stay, and mortality in both groups. CONCLUSIONS No significant trend was identified for an effect of GL on gut permeability. Decreased inflammation and endotoxemia did not translate into reduced infectious complications in severe acute pancreatitis. However, the study was underpowered to detect the aforementioned difference (trial registration: CTRI/2009/000945).