Recent studies have focused on the potential role of natural anticoagulants in modulating host responses to endotoxin. The natural anticoagulants that have drawn the greatest attention are antithrombin, protein C, and tissue factor pathway inhibitor (TFPI). Interest in this area is spurred by clinical and basic observations. On the clinical side, there is a correlation between low levels of protein C and antithrombin and a negative clinical outcome. The situation with TFPI is much more difficult to interpret because the majority of TFPI is associated with the blood vessel1 and changes in plasma levels can reflect altered distribution between the vessel wall and plasma. On the basic side, animal models of septic shock employing either endotoxin or Escherichia coli, usually performed by intravenous infusion of these agents, have shown that antithrombin, 2 protein C/activated protein C, 3 or TFPI4 can reduce the frequency of lethal responses in nonhuman primates and other animals. In general, these studies have found that, in addition to dampening the disseminated intravascular coagulation (DIC) associated with the endotoxin challenge, elevation of the natural anticoagulant levels also decreases the inflammatory response including IL-6 and IL-8 levels in the case of TFPI (see Creasey et al4) and antithrombin (see Minnema et al, this issue). Contrasting these reports are studies of human volunteers administered low doses of endotoxin: there was an increase in their coagulation response, but the administration of TFPI failed to alter the IL-6 levels or those of other markers of inflammation (see de Jonge et al, this issue). This discrepancy between the response of human volunteers and experimental animals to endotoxin infusion raises several questions that warrant some discussion. For instance, are the differences simply a matter of species, or are there differences in experimental design that could account for the different outcomes? Before dealing with this issue, it is worth reviewing a rapidly growing literature on the role of coagulation factors in activating cells and eliciting inflammatory responses. It is in this context that the potential role of natural anticoagulants in modulating these responses is most easily understood. When considering any in vivo results, it is important to bear in mind that altering the concentration of antithrombin or TFPI will diminish thrombin formation in response to endotoxin and that this will diminish the activation of protein C. Thus if activated protein C has antiinflammatory functions not replicated by the other inhibitors, elevation of the other natural anticoagulants could have unexpected negative effects on the regulation of both the coagulation and inflammation processes.