Tumor necrosis factor a (TNFa), a primary mediator of systemic responses to sepsis and infection, can be injurious to the organism when present in excessive quantities. Here we report that two types of naturally occurring soluble TNF receptors (sTNFR-I and sTNFR-II) circulate in human experimental endotoxemia and in critically ill patients and demonstrate that they neutralize TNFa-induced cytotoxicity and immunoreactivity in vitro. Utilizing immunoassays that discriminate between total sTNFR-I and sTNFR-I not bound to TNFa, we show that sTNFR-I-TNFa complexes may circulate even in the absence of detectable free TNFa. To investigate the therapeutic possibilities of sTNFR-I, recombinant protein was administered to nonhuman primates with lethal bacteremia and found to attenuate hemodynamic collapse and cytokine induction. We conclude that soluble receptors for TNFa are inducible in inflammation and circulate at levels sufficient to block the in vitro cytotoxicity associated with TNFa levels observed in nonlethal infection. Administration of sTNFR-I can prevent the adverse pathologic sequelae caused by the exaggerated TNFa production observed in lethal sepsis. vitro. Endogenous TNFa in plasma obtained from volunteers 90 min after receiving an endotoxin challenge was found to be significantly neutralized by 5 ng of rsTNFR-I or 500 ng of rsTNFR-II per ml. These experiments establish that physiologic concentrations of rsTNFR-I will significantly neutralize the cytotoxicity of levels of TNFa found endogenously and suggest that at least the higher concentra- tions of sTNFR-I detected in the circulation of critically ill patients (5-10 ng/ml) are sufficient to partially attenuate TNFa bioactivity, while these concentrations of rsTNFR-II are insufficient to inhibit TNFa cytotoxicity.