Cold agglutinins are commonly found in sera of healthy persons. They rarely become clinically apparent due to their activity at low temperatures. In these patients, cardiovascular operations requiring hypothermia can result in complications such as hemolysis, renal failure, and myocardial damage and can cause unexpected morbidity and mortality. The literature on cold-reactive proteins is reviewed, and methods of diagnosis and management related to cardiac surgery are suggested. Ideally all patients should be routinely tested preoperatively for the antibodies, and appropriate changes in cardiopulmonary bypass and myocardial management plans should be made in positive patients. Preoperative plasmapheresis may be a useful adjunct, especially in patients requiring operation under profound hypothermia and circulatory arrest. Currently, warm heart surgery appears to be the most expedient method. Unexpected detection of agglutination during operation or hemolysis after operation requires a specific treatment plan.