A 33-year-old man with inherited protein S deficiency and a 20-year history of deep and superficial venous thrombosis was admitted for treatment of extensive, acute, superficial venous thrombosis of the left lower extremity. Clinical response to intravenous heparin was very slow. After discovery of acquired antithrombin III deficiency superimposed on the protein S deficiency, he was given antithrombin III concentrates with the intravenous heparin. His response to therapy was accelerated. The development of acquired antithrombin III deficiency in patients with venous thrombosis may slow the response to standard anticoagulant therapy. Therapy of the thrombosis may be improved with administration of antithrombin III concentrates.