In cold autoimmune hemolytic anemia, the causative autoantibodies (cold agglutinins) are most reactive at low temperatures. The anti-I type of cold agglutinin is found in cold hemagglutination disease and in hemolytic anemia secondary to malignant lymphoma, leukemia, or atypical pneumonia. The anti-I type of cold agglutinin is found in many patients with infectious mononucleosis and in an occasional patient with other lymphoproliferative disorders. Paroxysmal cold hemoglobinuria, a disorder in which exposure to cold temperatures triggers massive hemolysis, is characterized by a unique biphasic cold autoantibody called the Donath-Landsteiner antibody. By way of summary and review of this and the two previous articles in this series, table 4 presents a practical approach to diagnosis of the autoimmune hemolytic anemias.