Thirty infants with intractable diarrhea of infancy (IDI) underwent small bowel biopsies in order to determine the extent and duration of small intestinal mucosal injury. The onset of the persistent diarrhea occurred prior to 3 months of age and continued for an average of 48 days prior to investigation. In 18 cases, no associated entities were found. Mucosal injury was invariably found in all 30 infants: grade IV injury in 11, grade III in eight, grade II in nine, and grade I atrophy in one. Disaccharidase activities were diminished and corresponded to the degree of atrophy. Lactase activity was diminished to a greater extent than sucrase and maltase. Significant, persistent mucosal injury existed for an average of six months in 16 of the 23 (70%) repeat biopsies. All infants were given an elemental diet (ED). Twelve of the 30 infants required parenteral nutrition (PN). These infants were gradually advanced to an oral elemental diet and maintained on this diet until histologic findings and disaccharidase levels were normal. Eighteen infants were fed and maintained on an elemental diet by mouth from time of admission until normal histologic findings and disaccharidases were found. No mortality occurred during management and follow-up. Twenty-two of the 28 infants in whom follow-up growth data were available excelled in weight and height velocity. The data suggest that prolonged injury to the small intestinal mucosa is a common finding in many cases of intractable diarrhea of infancy. Elemental diets should be started early in the course of protracted diarrhea in young infants, and may need to be continued for several months since histologic and enzymatic changes of the small intestine may persist for extended periods.