Treatment of rats with recombinant human TNF initially causes a marked decrease in food intake, a loss of body weight, and a negative nitrogen balance. These alterations normalize with continued twice daily intraperitoneal injections of the same dose. Rats tolerized to TNF in this manner are refractory to a lethal dose of TNF. Also, TNF-pretreated and -tolerized rats have prolonged survival and reversed histopathologic changes after injection of a lethal dose of endotoxin compared with control animals. The TNF-tolerant state is dependent on the dose of TNF used and the length of TNF pretreatment. TNF-induced tolerance is relatively short lived, being present 2-4 d after TNF pretreatment and dissipating by 2 wk. Rats made tolerant to endotoxin are also tolerant to a lethal dose of TNF. A bidirectional crossreacting tolerance exists between TNF and endotoxin. The mechanism of TNF tolerance is unclear, but it does not appear to be due to a humoral immune response or a perturbation of the uptake and clearance of injected TNF.