Chronic cold agglutinin disease (CAD) is mediated by monoclonal cold-reactive autoantibodies that bind to erythrocyte surface antigens, causing hemagglutination and complement-mediated hemolysis. Anemia is severe in one-third of patients (hemoglobin level 8.0 g/dL or lower). Cold-induced circulatory symptoms are present in more than 90% of patients and may be disabling. CAD not associated with overt lymphoma or other disease has traditionally been classified as primary or idiopathic. A monoclonal lymphoproliferative bone marrow disorder can, however, be demonstrated by flow cytometry in 90% and by histology in approximately 75% of these patients, characterized by clonal proliferation of CD20+, kappa+ B-cells.