Autoantibodies against red cells optimally reacting at 0 degree C, ie, CA, are normally found with low titers in the serum of human adults. High-titer CA may be induced by certain infectious agents, including M pneumoniae, EBV, CMV, and rubella virus, or may develop on the basis of chronic (malignant) B cell lymphoproliferation. The main clinical manifestation of cold agglutination is AIHA. Antigens and antibodies of cold agglutination are the best characterized reaction partners of a human autoimmune process. CA may recognize I and i antigens, which are lipid- and protein-linked branched and linear N-acetyl-lactosamine chains, respectively. They are precursors of the ABH blood group antigens and are converted into H by fucosylation. An alternative substitution by sialylation creates Gd, Fl, and probably Vo/Li antigens. CA with anti-Pr and anti-Sa specificities recognize 0-glycans with immunodominant sialyl groups on glycophorins. Several Pr subspecificities can be identified by chemically modified sialyl groups on glycophorins. Because CA in chronic lymphoproliferation are monoclonal antibodies, structure-specificity-interrelations of the antibodies could be identified by primary structure analyses of the N-terminal variable regions of H and L chains and by studies on CA idiotypes. Interrelations between distinct CA specificities and particular infectious agents could explain cold agglutination as a response to receptors for the agents or to the binding sites of antibodies against the agents. Interrelations also existing between certain CA isotypes (Ig classes and L chain types) and CA specificities could be a basis for the elucidation of the enigmatic etiology of chronic (malignant) monoclonal cold agglutination.