Phagocytosis of IgG-coated erythrocytes (EIgG) can depress several macrophage functions. Our previous studies have suggested that this macrophage dysfunction may be due to an oxidative stress caused by the interaction of hemoglobin-derived iron with superoxide and/or hydrogen peroxide. Since lysosomotropic agents are capable of altering iron handling by macrophages, the present study evaluated the ability of these agents to prevent the macrophage dysfunction and lipid peroxidation caused by a phagocytic challenge with EIgG. Elicited rat peritoneal macrophages showed a depression of PMA-stimulated hydrogen peroxide production, calcium ionophore-stimulated arachidonate release and Fc receptor-mediated phagocytosis. The lysosomotropic agents; chloroquine, quinacrine, ammonium chloride and methylamine all prevented the depression of hydrogen peroxide production and arachidonate release but did not alter the depression of phagocytic function. These agents also prevented the increase in lipid peroxidation products caused by a phagocytic challenge with EIgG. These results suggest that the ability of lysosomotropic agents to prevent some aspects of macrophage dysfunction after a phagocytic challenge may be due to their ability to block the oxidative stress caused by the challenge.