Patients with severe trauma injury are transiently exposed to increased serum concentrations of tumor necrosis factor- (TNF-). These patients are susceptible to the development of multisystem organ failure (MSOF) triggered by subsequent exposure to bacterial toxins either via infection or increased intestinal permeability. We simulated the cytokine response of trauma by infusing 0.8 or 8.0 µg/kg of TNF- (priming dose) into chronically catheterized rats. After 48 h, rats were challenged with endotoxin [lipopolysaccharide (LPS); 10 or 1,000 µg/kg]. Animals primed with either dose of TNF- and then challenged with 1,000 µg/kg of LPS demonstrated significantly increased mortality, mean peak serum concentrations of interferon- (IFN-), and blood lactate concentrations (P < 0.05) compared with nonprimed animals. Mean peak serum concentrations of IFN- and blood lactate concentrations were increased after challenge with 10 µg/kg of LPS only in animals primed with 8.0 µg/kg of TNF-. Priming with TNF- did not increase mortality after challenge with 10 µg/kg of LPS. These data suggest that both TNF- release and the subsequent exposure to bacterial toxins mediate the pathophysiological progression from trauma to subsequent MSOF.