In most cases, immune-mediated hemolysis occurs extravascularly and is associated with IgG antibodies on the surface of red cells. Rare syndromes include IgG antibodies that cause direct intravascular hemolysis, such as paroxysmal cold hemoglobinuria. Also rare are extravascular hemolytic syndromes caused by IgM polyclonal or monoclonal antibodies that demonstrate red cell agglutination at 3 degrees C, so-called cold antibodies. Because cold agglutinin disease has a high association with several lymphoproliferative disorders and IgM monoclonal gammopathies, its management differs significantly from that associated with warm autoimmune hemolytic anemia. This case-based presentation is designed to guide the reader to the diagnosis and to the initiation of prompt, effective therapy.