The studies that have been carried out to date suggest that protein S can function as a cofactor protein in the activated protein C catalyzed inactivation of Factor Va. This conclusion is supported by the observation that protein S and activated protein C can form a lipid bound complex that can inactivate Factor Va more rapidly than does soluble activated protein C. Protein S has a number of properties in common with other cofactor proteins. It has been isolated as a distinct entity from plasma, it has no known intrinsic activities, and its effect is maximal when it is bound to a lipid surface. Protein S appears to be important in the regulation of the plasma anticoagulant activity of activated protein C as well. This is supported by the lack of anticoagulant activity of activated protein C in protein S-depleted plasma and by the observation that protein S is important in the species specificity of the anticoagulant activity of the enzyme. Future work in this area is needed to ascertain if there are any clinical manifestations of protein S deficiencies that correlate with the cofactor activity that has been established.