The process of blood coagulation is mediated by activation of a series of serine-protease zymogens. The protein C (PC) anticoagulant pathway, one of the important pathways related to physiological thrombosis formation, includes PC, thrombomodulin (TM), endothelial PC receptor (EPCR), protein S (PS) and C4b-binding protein (C4BP). TM, mainly present in endothelial cells, is a cofactor for thrombin-catalyzed activation of PC, and the resulting activated PC (aPC) inactivates the blood coagulation cofactors factor Va and factor VIIIa in the presence of PS. PS, mainly synthesized in hepatocytes and endothelial cells, plays a critical role as a cofactor of anticoagulant aPC in the regulation of blood coagulation. The cofactor activity of PS for aPC is regulated by C4BP, a multimeric protein whose structure consists of seven α-chains (C4BPα) and a β-chain (C4BPβ). Sepsis is generally caused by infection by microorganisms, and patients with sepsis undergo drastic hemostatic changes, thought to be induced by lipopolysaccharide (LPS) and inflammatory cytokines. In this review, based primarily on our previous studies, we describe the LPS- and cytokine-induced changes in various proteins in the PC anticoagulant pathway that are related to the increased risk of thrombosis under sepsis. Furthermore, we discuss the potential of recombinant soluble TM (rsTM) as a possible remedy for sepsis.