Antithrombin III (ATIII) is the predominant naturally occurring inhibitor of serine proteases generated during blood coagulation [Rosenberg RD: Annu Rev Med 1978; 29: 367-378]. Since 1965, several assays have been developed that allow rapid and precise determination of ATIII in plasma. As a consequence, the existence of acquired ATIII deficiency in many pathologic conditions has been described. Acquired ATIII deficiency is based on decreased synthesis, increased loss or increased consumption, or induced by drugs. An inherited ATIII deficiency is associated with a lifelong tendency to venous thromboembolism. In contrast, the clinical significance of acquired ATIII deficiency has been less well defined. A precise estimate of the risk of thromboembolism in the acquired ATIII deficiency state cannot easily be provided, owing to the lack of studies in consecutive patients. In 1978, a purified human ATIII concentrate became available for clinical investigation. Despite numerous small studies, the value of ATIII replacement therapy in patients with acquired deficiency remains to be demonstrated.