The mitogenic properties of OKT3 (IgG2a) and anti-Leu 4 (IgG1), two monoclonal antibodies directed at the same surface antigen of human T cells, have been studied. Both antibodies, at subnanomolar concentrations, induced thymidine incorporation of comparable magnitude into human peripheral blood mononuclear cell cultures. Their mitogenicity reached peak values 3 days after stimulation, was totally inhibitable by monoclonal OKT11A antibody, and was strictly dependent on the presence of monocytes as auxiliary cells. Whereas mononuclear cells from all blood donors tested were proliferative to OKT3, cells from 12 of 30 donors (40%) were unresponsive to anti-Leu 4. The incidence of this unresponsiveness was significantly higher for cells from female than male donors, showing 60 and 20% nonresponders, respectively. Anti-Leu 4 unresponsiveness was found to be due to the inability of autologous monocytes to exert their auxiliary function; thus, lymphocytes from anti-Leu 4 nonresponders became mitogenically inducible by anti-Leu 4 after addition of monocytes from anti-Leu 4 responders, whereas lymphocytes from anti-Leu 4 responders failed to respond to anti-Leu 4 after supplementation of monocytes from anti-Leu 4 nonresponders. Considering the different immunoglobulin subtype of OKT3 (IgG2a) and anti-Leu 4 (IgG1), our results indirectly suggest that the auxiliary function of monocytes is mediated by their Fc receptors. Unresponsiveness to anti-Leu 4 could then be explained by the absence, paucity, or functional deficiency of monocytic Fc receptors for IgG1.