Background: Antithrombin III (AT III) deficiency is a rare disorder and thrombosis can be induced by a minor cause that does not normally lead to thrombosis, such as an external injury and surgery. Therefore, patients with AT III deficiency undergoing cardiac surgery that involves heparinization require careful perioperative management. Objective and Methods: From September 2013 through December 2023, we experienced 8 patients (1.92%) with AT III deficiency who underwent cardiac surgery and were managed with AT III replacement. By administration of AT III concentrate, preoperative AT III activity was maintained at ≥ 120% and postoperative AT III activity at ≥ 80%. Results: All five patients were treated successfully without postoperative complications such as hemorrhage or thrombosis. In a case of aortic valve stenosis in a hemodialysis patient, reoperation was performed 9 months after aortic valve replacement with a bioprosthetic valve. Pathological examination suggested that the deterioration was caused by a large amount of thrombus on the outflow side of the valve leaflet and not by iatrogenic calcification due to dialysis. Conclusions: In patients with AT III deficiency undergoing cardiac surgery, it is important to perform AT III replacement to achieve preoperative AT III activity ≥ 120% and postoperative AT III activity ≥ 80%, while the activated clotting time is maintained at > 400 s during cardiopulmonary bypass. In addition, long-term postoperative anticoagulant therapy is necessary in hereditary AT III deficiency patients with a history of thrombosis.