As a model of IgM-induced hemolytic anemia in man, human erythrocytes were sensitized with IgM antibody and coated with complement components, including C3 and C4, using human serum as a source of complement. These coated red cells were then interacted with monolayers of human mononuclear phagocytic cells (monocytes). Complement-coated red cells so bound could be displaced from their monocyte attachment site in a dose- and time-dependent manner by serum factors, including C3b inactivator (C3bINA). These factors were more efficient in inactivating red cell-bound complement components prior to interaction of the coated cells with monocytes. With large amounts of complement per erythrocyte, measured as membrane-bound C3, the ability of the serum inactivating factor(s) to remove the complement-coated red cells from the monocyte surface was compromised and persistently bound red cells were progressively phagocytosed. These studies implicate C3bINA in the displacement of complement-coated erythrocytes, formed from the interaction of IgM antibody and serum complement, from the hepatic macrophage in IgM-induced immune hemolysis. They suggest that both the concentration of complement components, especially on the erythrocyte surface, and the level of C3bINA and perhaps other inactivators may be important features regulating hemolysis in this disorder.