Previous reports have indicated that prostaglandins can inhibit certain immune mechanisms, particularly mitogen responsiveness and cell-mediated cytotoxicity of virus-infected or tumor cells. In this study an endogenous self-inhibitory mechanism for antibody-dependent cellular cytotoxicity (ADCC) with normal human peripheral blood mononuclear cells is described. This inhibition could be abrogated by the prostaglandin synthetase inhibitor indomethacin or by removing nylon wool-adherent cells but not platelets. ADCC inhibition was restored by adding exogenous PGE1, PGE2, or supernatant fluid from cultured plastic-adherent mononuclear cells. In contrast, supernatant fluid from adherent mononuclear cells cultured with indomethacin was not inhibitory for ADCC. These results suggest that peripheral blood mononuclear cells contain adherent cells, probably monocytes, which produce prostaglandins that inhibit the ADCC effector activity of normal peripheral blood lymphocytes. This may explain, in part, the wide variability of ADCC effector cell activity that has been reported previously. Monocyte proportions and/or activity may have profound effects on tests of ADCC effector cell activity in various disease states.