A brief exposure of murine peritoneal inflammatory macrophages to plasma histidine-rich glycoprotein (HRG; 77,000-81,000 MW) for 1-2 hr increased Fc gamma receptor (Fc gamma R) expression and phagocytic function in these cells. However, a continual culture of the cells without the presence of HRG for the next 18-48 hr resulted in down-regulation of Fc gamma R expression and phagocytic function. Similarly, HRG decreased Fc gamma RII expression in less differentiated human THP-1 monocytic cells during treatment for 18 hr, as determined by cellular ELISA and metabolic labelling. The molecular mechanism by which HRG regulates Fc gamma R expression is unknown. However, at a relatively high concentration (> 1 microgram/ml), HRG altered the cellular metabolism by increasing cellular protein synthesis but reducing protein secretion. These observations suggest a likely mechanism for the HRG-mediated reduction of Fc gamma R expression. A degraded HRG (40,000 MW) which possessed an identical N-terminal sequence as that of the native HRG was capable of decreasing macrophage Fc gamma R expression and phagocytosis. The results indicate that the functional domain of HRG responsible for binding to macrophages is localized to the N-terminal half.