Vasoactive intestinal peptide is a neuropeptide with potent modulatory activity on intestinal immunity and may be implicated in the pathogenesis of inflammatory bowel disease (IBD). Previous studies have reported abnormal morphology of vasoactive intestinal peptide-stained enteric nerves, in addition to increased, normal or decreased levels of extractable peptide in Crohn's disease (CD) and ulcerative colitis (UC) tissues. These observations have not been correlated with the amount of enteric nerve fibers or the degree of mucosal inflammation. The investigation was intended to determine whether abnormalities of vasoactive intestinal peptide in IBD are related to quantitative changes of enteric nerve fibers or mucosal inflammation, and whether they are specific for CD or UC. To do this, digitized morphometric analysis was applied to a large number of IBD and control colonic surgical specimens that were immunostained for vasoactive intestinal peptide and S100 protein and scored for severity of inflammation. The results showed that, as compared with controls, there is a marked decrease of vasoactive intestinal peptide-immunoreactive nerve fibers in the lamina propria and submucosa (P less than 0.0001), and of S100-immunoreactive nerve fibers in the lamina propria (P less than 0.0001) of patients with IBD. In the lamina propria but not the submucosa, the variation of decrease is significantly associated with the severity (P less than 0.0001) but not the type (P greater than 0.9) of IBD because it is detected in both CD and UC. We conclude that in IBD there is loss of mucosal neuropeptidic innervation that is intimately associated with inflammation. This loss probably represents a nonspecific event subsequent to damage to enteric nerve fibers but may contribute to disruption of local immunoregulation.