Excessive activation of the coagulation system leads to life-threatening disseminated intravascularcoagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. Wefound that caspase-11, a cytosolic LPS receptor,activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores andsubsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD poresmediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, orneutralization of phosphatidylserine orTF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1 andIL-1, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC. Copyright 2019 Elsevier Inc. All rights reserved.