Ligand-conjugated substrates were used to study mouse macrophage receptor-ligand interactions. Both resident and thioglycollate-elicited macrophages plated on substrates conjugated with mannans and horseradish peroxidase (HRP), ligands for the Man/GlcNAc receptor, lost their ability to phagocytose zymosan. In addition, these macrophages also lost their ability to phagocytose IgG-coated erythrocytes (E(IgG] via their Fc receptors (FcR). The abrogation of Fc receptor-mediated phagocytosis occurred as early as 4 hr after macrophage plating on HRP-coated substrates and was dependent on the amount of HRP conjugated to the substrate. Macrophages plated on those substrates showed a 70% reduction in E(IgG) binding and the same decrease (approximately 35%) in binding of 125I-labeled Fab fragment of monoclonal anti-IgG2b FcR antibody as macrophages plated on dinitrophenyl-anti-dinitrophenyl IgG immune complexes. We interpret these results as showing that modulation of macrophage mannose/GlcNAc receptors induces modulation of FcR.