The association of megacolon in adults and Hirschsprung's disease was reevaluated by the morphological assessment of the enteric nervous system. Whole-mount preparations of the resected colonic segments and an immunohistochemical treatment with the pan-neuronal marker protein gene product 9.5 allowed an optimal visualization of the entire intramural nervous plexus layers. The findings included different forms of intestinal neuronal malformations (hypoganglionosis, neuronal intestinal dysplasia, and heterotopic ganglia) apart from classic aganglionosis, thus indicating their etiologic relevance to the development of megacolon in adults.