Resident peritoneal macrophages from systemic lupus erythematosus (SLE)-prone strains, NZB, (NZB X NZW)F1 and MRL/MpJ-lpr/lpr mice, exhibited very low binding and phagocytosis of opsonized 51Cr-labeled sheep erythrocytes (EA) compared with cells from normal mice. Male BXSB mice, which also develop SLE, were not clearly defective in phagocytosis and binding of EA compared with C57B1/6J, the lowest of the "normal" mice tested, but were less effective than their normal female BXSB counterparts. The extent of the defect depended on the age of the animals tested. Young NZB/N mice showed hyperactive binding and phagocytosis and became defective about the time of disease onset. Even young (NZB X NZW)F1 and MRL/MpJ-lpr/lpr mice were defective and worsened with age. Increasing numbers of resident peritoneal macrophages were recovered from the autoimmune mice as they aged. Near normal binding and phagocytosis of EA could be effected by stimulation in vivo by injection of killed Corynebacterium parvum. Resident peritoneal macrophages from congeneic xid (X-linked immune deficiency gene) bearing NZB and (NZB X NZW)F1 mice showed normal reactivity. Binding and phagocytosis of EA was Fc mediated and was inhibited by pretreatment with large doses of heat-aggregated human gamma-globulin. Defective macrophage Fc receptor binding or turnover may play an important role in the observed manifestations of autoimmune disease in murine SLE.