Studies of the pathophysiology of autoimmune hemolytic anemia emphasize the important role of cell membrane receptors for various immunologically active proteins in the clearance of foreign or damaged particulate materials from the blood stream. Receptors for the Fc fragment of immunoglobulin G (IgG) antibodies and for opsonically active fragments of the third component of complement on cells of the reticuloendothelial system function to clear from the circulation erythrocytes coated with these proteins. Our studies show the key role that complement plays in the biologic function of immunoglobulin M (IgM) antibodies like many cold agglutinins and isoagglutinins. They show how complement may contribute to IgG-mediated cell destruction. The IgG and IgM antibodies have dramatically different effects on erythrocyte survival, and these effects explain many of the clinical differences between IgG- and IgM-mediated hemolytic diseases. These studies also show that many of the factors that influence the course of autoimmune hemolytic anemia act by altering the level of immunologic sensitization required to mediate clearance.