The effects of natural and recombinant human gamma-interferon (IFN-gamma) on mouse monoclonal antibody-dependent cellular cytotoxicity (ADCC) mediated by U937 human monocytic-like cells were examined. The efficiency of mouse monoclonal antibody of different isotypes in inducing ADCC was also compared. The number of receptors for the Fc portion of immunoglobulin G (IgG) (FcR) for mouse IgG2a and IgG3 on U937 cells, as detected by IgG antibody-sensitized erythrocyte rosette formation, was significantly enhanced by IFN-gamma. In contrast, FcR for mouse IgG1 and IgG2b were not detected even after IFN-gamma stimulation. U937 cell-mediated ADCC against sheep or ox red blood cell targets was minimal. However, after incubation with human purified IFN-gamma, U937 cells exhibited increased activity in IgG2a- and IgG3-dependent lysis, whereas their activity in IgG1- and IgG2b-dependent lysis was low. ADCC stimulated by IFN-gamma was inhibited by Protein A. When mouse peritoneal exudate cells were used, FcR for all IgG isotypes were easily detected, and all IgG isotypes mediated ADCC. Taken together, these results indicate that IFN-gamma induces U937 cell ADCC with mouse IgG2a and IgG3 partly through augmentation of FcR expression. Recombinant IFN-gamma showed the same effect as natural IFN-gamma. These effects of IFN-gamma were completely abrogated by anti-IFN-gamma serum but not by anti-IFN-alpha or normal rabbit serum. Addition of polymyxin B or lipopolysaccharide did not affect the activity of IFN-gamma.