To evaluate the feasibility of using a monoclonal anti-Fc receptor antibody to alter Fc receptor function in vivo, the disappearance of radiolabeled human serum albumin-rabbit anti-human serum albumin (HSA-anti-HSA) complexes was studied in mice before and after the infusion of 2.4G2, a monoclonal antibody (developed by J. Unkeless). 2.4G2 specifically binds to Fc receptors on mouse macrophages. Under standardized conditions, 6.1% of an i.v. administered dose of anti-HSA was sequestered in the liver of B6/D2J mice. When HSA-anti-HSA complexes were administered, 53.4% were sequestered. If 8 micrograms/g body weight of 2.4G2 was infused i.p. 1.5 hr before HSA-anti-HSA, only 13.7% of the infused complexes were sequestered in the liver. The inhibition in Fc receptor-mediated sequestration produced by this dose of antibody persisted for at least 24 hr. A dose of 1 to 2 micrograms/g was sufficient to inhibit sequestration by 50%. Animals receiving daily injections of 2.4G2 cleared immune complexes from their blood much more slowly than untreated animals. Because 2.4G2 was not cytotoxic to peritoneal macrophages in vitro in the presence of serum, and because comparable inhibition of Fc receptor function was observed in vivo in C5-deficient mice, blockade of function does not depend upon complement-mediated lysis of macrophages. The maximal degree of inhibition of Fc receptor function obtained by using intact 2.4G2 was about twice that observed by using Fab fragments of 2.4G2 to block receptors. In addition to its effect on Fc receptor function, 2.4G2 also had a small but significant inhibitory effect upon the clearance of 125I-labeled heat-aggregated HSA by the mononuclear phagocyte system both in intact and C5-deficient mice. We conclude that 2.4G2 is a potent inhibitor of IgG Fc receptor-mediated immune clearance in vivo.