Background & aims: Hepatic dysfunction is one of the most frequent complications of parenteral nutrition. Very low birth weight (VLBW) infants are more sensitive to liver injury due to physiological immaturity. Our studies in animals showed that glutamine supplementation could attenuate TPN-associated liver injury. The aim of study was to investigate whether parenteral glutamine supplementation can improve hepatic tolerance in VLBW infants. Methods: We performed a double-blind, randomized, and controlled clinical study to investigate whether parenteral glutamine supplementation can improve hepatic tolerance in VLBW infants. Thirty VLBW infants at two children's centers were randomly assigned to either a control group or a glutamine-supplemented group. The primary endpoints were hepatic function and mortality. The secondary endpoints were the time to achieve full enteral nutrition, episodes of gastric residuals, duration of parenteral nutrition, weight and head circumference gain, length of hospitalization, and days on ventilator. Results: The serum levels of aspartate aminotransferase (AST) and total bilirubin (Tbi) were decreased after PN in the glutamine-supplemented group (P < 0.05). No deaths occurred in this study. Four infants assigned to the control group and two infants in the glutamine-supplemented group were withdrawn from the study, according to intention to treat: relative risk [RR]: 1.182; 95% confidence interval [CI]: 0.937-1.490. Conclusions: Parenteral glutamine supplementation can improve hepatic tolerance in very low birth weight infant, suggesting a hepato-protective effect. © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.