Cold hemagglutinin disease is infrequently recognized before complications ensue. We describe a patient with chronic cold hemagglutinin disease who sustained an acute hemolytic crisis during a routine operative procedure in a cool operating room. Cold agglutinins were present during routine preoperative blood cross matching with the Coombs' test positive for C3d. Analysis of the offending cold agglutinin revealed a high-titer monoclonal IgM-kappa antibody with anti-I specificity and broad thermal amplitude. Major complications from the presence of cold agglutinins have been poorly documented and are often thought to be of only theoretic concern. This case and literature review show that such complications may occur and emphasize the importance of careful preoperative plans when the Coombs' test suggests that cold agglutinins exist.