Protein S (PS) is a vitamin K-dependent glycoprotein produced in the liver and circulates at levels of 20 ug/ml in plasma. PS is a single chain molecule of 69kD that acts as a cofactor in the proteolytic inactivation of factors VIIIa and Va by activated Protein C (APC). Approximately 60% of PS in plasma circulates as a complex with C4-binding protein (C4BP). Only the uncomplexed or “free” form of PS has cofactor activity and these forms can be quantified in plasma afterprecipitating the complexed form with cold polyethylene glycol precipitation. PS is subject to cleavage by thrombin resulting in a loss of cofactor activity. Patients with deficiencies of Protein S (quantitative and qualitative) are generally believed to be at risk of vascular thrombosis.