Pathology reports on neonatal necrotizing enterocolitis (NNEC) rarely consider its effects on the enteric nervous system (ENS). Thus, the aim of this study has been to perform a two-dimensional assessment of neuropathologic lesions within the three ganglionated plexuses of the intestinal wall by means of whole-mount immunohistochemistry. Resected segments of ileum and colon affected by acute NNEC were submitted to immunohistochemical procedures using antibodies against neuronal (protein gene product 9.5) and glial (protein S-100, glial fibrillary acidic protein) proteins. Examination of the myenteric plexus and external submucosal plexus revealed a noticeable reduction in glial cells concomitant with the gradual deterioration of nerve cells, both findings predominating in the antimesenteric intestinal circumference, where ischemic lesions tend to appear first. The most severe damage of nervous tissue was observed in the plexus submucosus internus dependent on the depth of mucosal injury. The destroyed ganglia appeared like "empty baskets" (residual tangles) and housed deteriorated nerve and glial cells. Taking the anatomy of the intestinal vascular blood supply into consideration, the characteristic topography of neuropathologic lesions gives further support to an ischemic event within the cascade of different pathogenetic factors culminating in NNEC. Moreover, the demonstrated alterations of the ENS and their potential adverse effects on intestinal motility and neuroimmunologic interactions may contribute to the complex pathogenesis of NNEC, which remains a field of further investigation.