Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants. However, despite significant morbidity and mortality the etiology and pathogenesis of NEC is poorly understood. Evidence suggests that ileal pro-inflammatory mediators such as IL-18 contribute to the pathology associated with this disease. In addition, we have previously shown that up-regulation of TNF- in the liver is correlated with ileal disease severity in a neonatal rat model of NEC. Using a neonatal rat model of NEC, we evaluated the incidence and severity of ileal damage along with the production of both hepatic and ileal pro-inflammatory cytokines in animals injected with (Anti-TNF-; n = 23) or without (NEC; n = 25) a monoclonal anti-TNF- antibody. In addition, we assessed changes in apoptosis and ileal permeability in the NEC and Anti-TNF- groups. Ileal damage was significantly decreased and the incidence of NEC was reduced from 80% to 17% in animals receiving anti-TNF-. Hepatic TNF-, and hepatic and ileal IL-18 were significantly decreased in pups given anti-TNF- compared to those sham injected. In addition, ileal luminal levels of both TNF- and IL-18 were significantly decreased in the Anti-TNF- injected group. Ileal paracellular permeability and the pro-apoptotic markers Bax and cleaved caspase-3 were significantly decreased in the Anti-TNF- group. These data show that hepatic TNF- is an important component for the development of NEC in the neonatal rat model, and suggest that anti-TNF- could be utilized as a potential therapy for human NEC.