TNF alpha contributes to the necrotizing enterocolitis (NEC) pathogenesis. To date, this clinical entity of neonates was never described in HIV-infected children. In 15 HIV-positive children with histological evidence of various intestinal lesions resembling NEC, we have studied serum TNF alpha and soluble TNF receptor concentrations by ELISAs, and archived paraffin embedded intestinal tissues by in situ hybridization with DIG-labeled RNA probes for TNF alpha messenger transcripts. We found increased levels of TNF alpha and soluble receptors, proving TNF alpha system activation. We detected TNF alpha messenger transcripts in all cases, regardless of the presence of microbial pathogens at intestinal level. Since HIV can infect many cells of the gastrointestinal tract, also triggering the secretion of TNF alpha, we concluded that factors contributing to NEC pathogenesis in HIV-infected children are complex. At least the nutritional and immunological status are involved, other viral co-infections, opportunistic microbes (such as mycobacteria), and pathogenic activities of HIV. All together enhance both circulating TNF alpha system and its cytotoxic effects at intestinal level.