Red cell autoantibodies, multiple immunoglobulin classes, and autoimmune hemolysis. The effects and interrelationships of multiple immunoglobulin coating (i.e., increased red cell [RBC]-bound IgM and/or IgA in addition to IgG) were investigated in 404 patients with warm-reactive RBC autoantibodies on 590 occasions. Multiple immunoglobulins were detected by enzyme-linked direct antiglobulin tests in 218 samples (37%), but in only 87 (15%) by agglutination methods. Differences in populations were examined by chi-square, with p less than 0.005 being required for significance because of the multiple tests. Compared with IgG coating alone, multiple immunoglobulins were significantly associated with larger quantities (greater than 800 molecules/RBC) of IgG, multiple IgG subclasses, IgG3 and C3d bound to the cells, and with serum haptoglobin levels of less than 0.1 g per L. The latter association was still significant when higher levels of RBC-bound IgG and subclass pattern were taken into account. In samples with multiple immunoglobulin coating, there was no significant relationship (p greater than 0.05) between haptoglobins of less than 0.1 g per L and either C3d or multiple IgG subclasses. It was concluded that multiple immunoglobulin coating, even when undetected by agglutination methods, is a major cause of hemolysis: it is part of a more generalized autoimmune response and acts with other factors such as the quantity of bound IgG, the IgG subclass pattern, and complement; it also has an important hemolytic effect in its own right. 