Abstract-The protein C system provides important control of blood coagulation by regulating the activities of factor VIIIa (FVIIIa) and factor Va (FVa), cofactors in the activation of factor X and prothrombin, respectively. The system comprises membrane-bound and circulating proteins that assemble into multi-molecular complexes on cell surfaces. Vitamin K-dependent protein C, the key component of the system, circulates in blood as zymogen to an anticoagulant serine protease. It is efficiently activated on the surface of endothelial cells by thrombin bound to the membrane protein thrombomodulin. The endothelial protein C receptor (EPCR) further stimulates the protein C activation. Activated protein C (APC) together with its cofactor protein S inhibits coagulation by degrading FVIIIa and FVa on the surface of negatively charged phospholipid membranes. Efficient FVIIIa degradation by APC requires not only protein S but also intact FV, which like thrombin is a Janus-faced protein with both procoagulant and anticoagulant potential. In addition to its anticoagulant properties, APC has antiinflammatory and antiapoptotic functions, which are exerted when APC binds to EPCR and proteolytic cleaves protease-activated receptor 1 (PAR-1). The protein C system is physiologically important, and genetic defects affecting the system are the most common risk factors of venous thrombosis. The proteins of the protein C system are composed of multiple domains and the 3-dimensional structures of several of the proteins are known. The molecular recognition of the protein C system is progressively being unraveled, giving us new insights into this fascinating and intricate molecular scenario at the atomic level. Key Words: factor V Ⅲ protein C Ⅲ protein S Ⅲ thrombomodulin P latelet-dependent primary hemostasis and blood coagulation have evolved as important defense mechanisms against bleeding. The initial occlusion of a vascular lesion is provided by the formation of the platelet plug. 1 This is temporally coordinated with the initiation of the coagulation system by the exposure of tissue factor (TF) to blood and the subsequent binding to TF of circulating factor VIIa (FVIIa). 2 The FVIIa-TF complex efficiently converts factor IX (FIX) and factor X (FX) to active enzymes FIXa and FXa, which together with factor VIIIa (FVIIIa) and factor Va (FVa), respectively, propagate the coagulation process (Figure 1). Factor VIII (FVIII) and factor V (FV) circulate in blood as high-molecular-weight inactive procofactors, which are converted into their active forms, FVIIIa and FVa, early during the coagulation process by thrombin or FXa. FVIIIa and FVa bind to negatively charged phospholipid membranes, eg, on activated platelets, and form complexes with FIXa and FXa, respectively. 3-5 The FIXa-FVIIIa complex (tenase) activates FX, whereas the FXa-FVa complex (prothrombinase) converts prothrombin to thrombin. In both the tenase and the prothrombinase complexes, the cofactors increase the catalytic efficiency of the respective enzyme by several orders ...