Nutritional depletion increases the risk for postoperative complications. The intestinal barrier may be important in the underlying pathophysiologic mechanism. In this study, 26 patients were evaluated to determine whether nutritional depletion was related to gut integrity and intestinal morphology. Nutritional depletion was estimated by calculating percentage ideal body weight (PIB) or percentage ideal fat free mass (PIFFM). To assess gut integrity, a lactulose/mannitol (L/M) test was performed. Duodenal biopsies were taken, and villous height, crypt depth, number of IgA-producing plasma cells, intraepithelial lymphocytes (IELs), and proliferating index were determined. The L/M ratio was increased, and villous height was decreased in depleted patients. Depletion was not associated with differences in the number of immune cells or proliferating index. The number of IgA-producing plasma cells was positively correlated with the L/M ratio. This study shows that nutritional depletion is associated with increased intestinal permeability and a decrease in villous height.