SignificanceAlthough it has long been known that inflammatory immune responses are associated with death of cells through necrosis, the mechanisms controlling this process are not yet well understood. Recently a type of programmed inflammatory cell death, necroptosis, has been discovered. In this paper we reveal previously unidentified molecular mechanisms that operate to induce this form of cell death. Our results indicate that in order to undergo necroptosis, immune cells must produce and receive signals from the key immune regulator, interferon. Such interferon-dependent necroptosis of immune cells drives acute inflammatory pathology in a mouse model of sepsis. This work highlights the intimate connection between cell death and inflammation, and may lead to new understanding and treatment of inflammatory pathologies.