The aim of this study was to evaluate possible changes in the neuropeptide innervation pattern of the remaining porcine ileum following 75% proximal resection of the small intestine. Three-month-old piglets were operated on and two months postoperatively full-thickness specimens of the proximal part of the distal ileum wall were taken. Age-matched 3- and 5-month-old unoperated piglets were used as controls. The number and intensity of VIP-, galanin-, enkephalin-, substance P-, and somatostatin-containing nerve fibers were estimated in sections processed for immunofluorescence microscopy and subjected to quantitative scoring. The VIP-, galanin-, and enkephalin-immunoreactive fibers of the circular muscle layer and villi were also quantitated by computer-assisted morphometry. The number and intensity of VIP-immunoreactive fibers in the mucosa and circular muscle layer markedly decreased after resection as compared to 3-month-old and 5-month-old controls (P < 0.05). The galanin immunoreactivity index decreased significantly after resection in the circular muscle layer as compared to both control groups (P < 0.05). The increase in the number of enkephalin-immunoreactive nerve fibers that normally occurred from 3 to 5 months of age was inhibited by the resection. We were not able to see any differences in somatostatin or substance P immunoreactivity between the groups. The results suggest that massive resection induces significant changes in the neuropeptide-containing innervation of the remaining small intestine. These findings are compatible with altered motor activity and mucosa function in the remain intestine.