We investigated the cytotoxicity of human monocytes mediated by two types of receptors for the Fc portion of IgG, Fc gamma RI and Fc gamma RII. Erythrocytes sensitized with human IgG (EA-human IgG) were used to assay Fc gamma RI function, and erythrocytes sensitized with mouse IgG1 (EA-mouse IgG1) were used to assay Fc gamma RII. Both types of Fc gamma R were observed to mediate antibody-dependent cell-mediated cytotoxicity (ADCC), which was further characterized by using different monoclonal anti-Fc gamma R antibodies (MoAb) and monomeric IgG. Lysis of EA-human IgG was inhibited by both monomeric human IgG and mouse IgG2a in a dose-dependent way, and also by anti-Fc gamma RI MoAb 10.1. Cytolysis of EA-mouse IgG1 was inhibited by monomeric mouse IgG1 and by two anti-Fc gamma RII MoAb, IV.3 and CIKM5. Antibodies of the mouse IgG2b isotype affected neither type of ADCC. The effectiveness of cytotoxicity mediated by either of the Fc gamma R was studied by means of targets sensitized with a calibrated number of IgG molecules. At least 20 times more IgG molecules per target cell were necessary to obtain half-maximal cytotoxicity mediated by Fc gamma RII than for Fc gamma RI-mediated cytolysis. Furthermore, the previously described polymorphism of Fc gamma RII was also reflected in Fc gamma RII-dependent cytotoxicity. These studies demonstrate that Fc gamma RII can mediate ADCC, although a higher degree of target cell sensitization is required than for Fc gamma RI-mediated ADCC.