Cold agglutinins (CAs) are autoantibodies that react reversibly with red blood cells (RBCs) at temperatures of, or below, the thermal amplitude for agglutination. This results in increased blood viscosity and sludging of RBC, and may impair perfusion to various organ systems. Although this phenomenon appears rarely in the clinical arena, the incidence of CA is increased substantially in cardiac surgery due to the routine use of hypothermia for organ preservation and systemic metabolic reduction. Once activated, CA are associated with microvascular occlusion, hemolysis, complement fixation, renal and hepatic insufficiency, cerebral insult, and myocardial infarction. Complications from CA may be minimized with appropriate screening, detection, and management in the perioperative period. A prototypical case is described, and pertinent issues regarding CA are reviewed.