A method and device is described for direct removal of heparin from whole blood during extracorporeal therapy. In clinical situations where the blood is heparinized to prevent clotting in the extracorporeal circuit containing e.g., a hemodialysis cartridge or a heart-lung machine, it would be desirable to eliminate the systemic heparinization of the patients. The extracorporeal circuit contains a device having antithrombin III immobilized and inserted between the outlet port of the primary extracorporeal device, such as the hemodialysis cartridge or heart-lung machine and the patient. When the heparinized blood comes in contact with the immobilized antithrombin III, heparin is removed and the reperfused blood is substantially free of heparin. The advantage of the system lies in the fact that heparin is removed from the blood rather than neutralized. This helps overcome the adverse reactions and side effects associated with the use of heparin anticoagulation.