Activation of coagulation by tissue factor (TF) is frequently observed in sepsis syndrome and is documented in certain viral hemorrhagic fevers. Coagulation protease complexes signal by activating the G-protein coupled, protease-activated receptors that regulate inflammation. Blockade of TF attenuates lethality in experimental models of Ebola virus infection but – similar to findings in bacterial sepsis – reduction of inflammation, rather than attenuation of coagulation, predicts survival of treated animals. Thus, targeting TF appears to aid the antiviral immune response in hemorrhagic fevers, and further studies are encouraged to define how TF-dependent signaling regulates immunity.