TNF influences morbidity and mortality during the course of endotoxemia. However, the complex pleiotropic functions of TNF remain poorly understood. We evaluated how hepatic induction of NFB and TNF influence survival and hepatocellular death in a lethal murine model of endotoxic shock. Using dominant-negative viral vectors to inhibit the IKK complex, we demonstrate that the liver is a major source of TNF during the course of lethal endotoxemia and that IKK (but not IKK) is predominantly responsible for activating NFB and TNF in the liver following LPS administration. Using TNF knockout mice and hepatic-specific inhibition of IKK, our studies demonstrate that the status of TNF and NFB balances necrotic and apoptotic fates of hepatocytes in the setting of endotoxemia. In the presence of TNF, inhibiting hepatic IKK resulted in increased survival, reduced serum proinflammatory cytokines, and reduced hepatocyte necrosis in response to a lethal dose of endotoxin. In contrast, inhibiting hepatic IKK in TNF knockout mice resulted in decreased survival and increased caspase 3-mediated hepatocyte apoptosis following endotoxin challenge, despite a reduced pro-inflammatory cytokine response. In the presence of TNF, NFB-dependent hepatocellular necrosis predominated, while in the absence of TNF, NFB primarily influenced apoptotic fate of hepatocytes. Changes in JNK phosphorylation following LPS challenge were also dynamically affected by both IKK and TNF, however, this pathway could not solely explain the differential outcomes in hepatocellular fates. In conclusion, our studies demonstrate that induction of NFB and TNF balances protective (antiapoptotic) and detrimental (proinflammatory) pathways to determine hepatocellular fates during endotoxemia.