Cold agglutinin (CA) reacts reversibly with red blood cells at a low temperature and may cause thromboembolism of various organs. Therefore, special consideration is required in patients with cold agglutinin disease (CAD) undergoing cardiovascular surgery requiring hypothermia. Case 1: A 71-year-old man with elevated CA was scheduled to undergo total aortic arch replacement. Preoperatively, the patient received double filtration plasmapheresis to reduce CAs. The operation was performed at a higher temperature than the patient's thermal amplitude (TA) of 30 degrees C. Case 2: A 72-year-old man with CAD underwent a coronary artery bypass grafting. The patient's TA was 32 degrees C. The operation was performed on the beating heart with normothermic cardiopulmonary bypass. We performed an agglutination test at the temperature of 24 degrees C using the blood sample from the cardiopulmonary bypass circuit and no signs of agglutination were found. In both cases, no symptom of microembolism due to cold agglutination was recognized. This may indicate the possibility that the clinical risk is smaller than the risk recognized in vitro analysis. However, no safety standards for perioperative management of patients with CA are clearly established. Generally, it is more important to figure out the TA and to prevent the low-temperature exposure below the TA. In cases of normothermic procedures, further consideration for cerebral and myocardial protection is important.