We studied the distribution of mucosal neuroendocrine (NE) cells in the colon from 13 patients with Hirschsprung's disease (HD) and from 8 controls. Immunohistochemical studies were carried out using monoclonal and polyclonal antibodies against chromogranin A and synaptophysin (general markers of NE cells), 5-hydroxytryptamine (5-HT) (a marker of amine), peptide YY (PYY), and somatostatin (markers of neuropeptides). Chromogranin A immunoreactive cells were significantly increased in the aganglionic bowel compared with ganglionic bowel and controls (P less than .05). There was an increase in the number of synaptophysin immunoreactive cells in the aganglionic bowel compared with ganglionic bowel and controls but the results were not statistically significant. 5-HT immunoreactive cells were also significantly increased in the aganglionic bowel compared with ganglionic bowel and controls (P less than .05). The immunostaining for PYY demonstrated abundance of this NE cell type in the aganglionic bowel and this was highly significant compared with ganglionic bowel and controls (P less than .001). There was a significant increase in somatostatin immunoreactive cells in the aganglionic bowel compared with ganglionic bowel (P less than .01). The increase in neuroendocrine cells was found over the entire length of the aganglionic segment in rectosigmoid HD as well as in long-segment HD. These results demonstrating the increased levels of NE cells in the mucosa of aganglionic colon suggest that the NE cells may have a role in regulating the sustained contraction of the aganglionic intestine in HD.