Appropriate anticoagulation is essential for safe cardiopulmonary bypass (CPB). Two patients with infective endocarditis were scheduled for valve replacement. After an intravenous heparin injection for the CPB, the increases in the activated clotting time (ACT) in both patients were less than expected. Subsequent additional heparin administration failed to maintain a sufficient ACT for the CPB, and antithrombin III (AT III) tests during the CPB revealed low activities in both patients. Heparin resistance, due to consumption of circulating AT III as a result of infective endocarditis or prior heparinization, was postulated. While fresh frozen plasma (FFP) could not be timely administered in the first patient, ACT was successfully prolonged after the administration of FFP in the second. It is strongly suggested that adequate management of heparin resistance should be prepared for patients with infective endocarditis who require CPB.