Nutrients in the lumen of the small intestine may cause the release of enteric hormones which directly or indirectly stimulate intestinal mucosal growth. Male Sprague-Dawley rats with either an intact small bowel or following jejunal resection were maintained on total parenteral nutrition (TPN). C-terminal octapeptide-cholecystokinin alone or combined with secretin, or glucagon alone were added to the intravenous nutrient solution and continuously infused. Control rats received only TPN or gastric infusion of isocaloric amounts of TPN solution. After 7 days, intestinal hypoplasia was noted in rats with an intact bowel maintained on TPN alone compared with the gastrically infused group. TPN did not maintain the proximal-distal gradient of mucosal mass. Continuous intravenous infusion of octapeptide-cholecystokinin alone and together with secretin in rats maintained on TPN significantly stimulated small bowel mucosal growth, partially restoring the proximal-distal gradient. Glucagon infusion did not stimulate mucosal growth. Rats with a jejunal resection and maintained on TPN for 7 or 14 days failed to develop mucosal hyperplasia of the ileum in contrast to rats given the TPN solution intragastrically. Continuous intravenous infusion of octapeptide-cholecystokinin in rats maintained on TPN after jejunal resection caused significant mucosal growth in the ileum compared with the rats maintained on TPN alone, but not to the extent seen in gastrically fed animals. Intravenous infusion of octapeptide-cholecystokinin stimulates small-bowel mucosal growth. Secretin appears to have an additional effect when given together with octapeptide-CCK. Although a direct trophic action by these hormones on the intestinal mucosa is possible, this effect is more likely mediated via stimulation of pancreaticobiliary secretions.