Polyagglutination, although an uncommon phenomenon in transfusion medicine, is becoming increasingly recognized as a potential pitfall in correct ABO typing and can hinder the rapid allocation of accurately crossmatched blood products. Polyagglutination refers to erythrocytes which demonstrate agglutination with the majority of adult sera upon initial ABO crossmatch testing. Most types of polyagglutination involve alteration of red cell surface antigens through microbial enzymatic activity in patients with sepsis, and subsequent interaction of these newly exposed 'cryptantigens' with naturally occuring IgM antibody which is present in most adult sera. Less common variants include essential inborn variations in red cell development, and have been associated with myelodysplastic syndromes, congenital anemias, and various leukemias; it has been suggested that patients shown to possess these types of polyagglutination may benefit from increased hematologic surveillance. Recognition of polyagglutination in these settings is important to allow successful resolution of ABO typing discrepancies and permit efficient administration of appropriate blood products to these patients, who are often quite ill. The classification and method of laboratory recognition of polyagglutination is reviewed.