Ganglioneuromas are complex tumors that arise in peripheral ganglia and are composed of well-differentiated neurons, nerve processes, Schwann cells, and enteric glial cells. The term ganglioneuromatosis (GN) denotes a regional or segmental proliferation of ganglioneuromatous tissue. This report describes an 8-year-old mixed breed horse with GN in a 25-cm segment of small colon. Grossly, the lesion consisted of numerous sessile to pedunculated nodules extending from the serosal surface. Histologic examination revealed the nodules to consist of fascicles of spindle-shaped cells consistent with Schwann cells, clusters of neurons, supporting enteric glial cells, and thick bands of perineurial collagen. Most of the nodules coincided with the location of the myenteric plexus and extended through the outer layer of the tunica muscularis to the serosal surface. Neuronal processes were demonstrated within the lesion with electron microscopy. With immunohistochemistry neurons were positive for neuron specific enolase (NSE) and S-100 and the Schwann cells and enteric glial cells were positive for S-100 and glial fibrillary acidic protein (GFAP). The pathogenesis of GN is poorly understood. GN, although rare, should be included in the differential diagnosis of gastrointestinal tumors in the horse.