Protein S is a vitamin K-dependent cofactor for the anticoagulant and the profibrinolytic effects of activated Protein C. Two forms of Protein S are present in plasma: free Protein S (40%), and Protein S linked to the complement C4b-binding protein (C4BP) (60%). Only free Protein S has functional cofactor activity.

Protein S deficiency may be hereditary or acquired. Acquired deficiency may be observed during pregnancy, oral anticoagulant therapy, oral contraceptive use, in liver disease, in newborn infants as well as in other clinical conditions. Deficiency of Protein S has been associated with a high risk of developing venous thromboembolism especially in young people.