Abstract Antithrombotic effect of heparin and a synthetic thrombin inhibitor, MD-805, was studied in experimental antithrombin III (AT III)-deficient animals which were prepared by intravenous injection of anti-AT III δ-globulin. The reduction of plasma AT III levels accelerated venous thrombosis in rats which was induced by insertion of a stainless steel wire coil into the inferior vena cava, but it gave no effect on the development of thrombin-induced acute pulmonary thromboembolism in mice. In these animals with lowered AT III levels (about 20 % of control mice and about 60 % of control rats), heparin was no longer effective in preventing thrombus formation, in contrast to MD-805 which was still effective regardless of plasma AT III levels. MD-805 was also effective in preventing the increase in complexed forms of AT III and the decrease in free (active) form of AT III in plasma of these thrombosed animals, while heparin gave no effect on these changes in plasma AT III profile. These findings strongly suggest the clinical usefulness of MD-805 in treatment of thrombotic disorders which were often accompanied by low plasma AT III levels.