Inherited antithrombin III (ATIII) deficiency causes a life-long tendency to venous thromboembolism, which is often recurrent and may be life-threatening. In contrast, the clinical importance of acquired ATIII deficiency, whether spontaneous or associated with estrogen-containing oral contraceptive treatment, remains uncertain. Moderately reduced ATIII activity before or immediately after surgery is neither sensitive nor specific for a high risk of postoperative venous thromboembolism (VTE), while moderately reduced ATIII activity during heparin treatment for VTE fails to indicate an unusually large heparin requirement or to predict recurrence. In the absence of good clinical trials, the value of ATIII replacement therapy also remains obscure; its use in congenital deficiency is largely based on anecdote, and while it may cause more rapid correction of the hemostatic defect in patients with disseminated intravascular coagulation (DIC), any improvement in morbidity or mortality resulting from ATIII replacement remains to be demonstrated.