Cytophilic activity for macrophages was shown to be a property possessed by most, if not all, of the complement binding 7S gamma(2)-population of guinea pig antibodies. Cytophilic antibodies were also demonstrated in rabbit and mouse antisera to sheep red cells. While each species antibody best sensitized homologous macrophages, cross species sensitization was also observed. The binding site for macrophages resides on the Fc fragment, therefore, on the H chains, and is destroyed by pepsin hydrolysis or reduction and alkylation. The binding reaction is reversible with a high rate of dissociation at 37 degrees C. Cytophilic activity is not complement dependent, and was shown to be that property of opsonizing antibody which provides the receptors that permit the binding of the antibody to the macrophage cell membrane in preparation for phagocytosis.