The in vitro effects of methotrexate, vincristine, dexamethasone and adriamycin to modulate the antibody dependent cellular cytotoxicity (ADCC) reaction and secretion of superoxide (O2-) and hydrogen peroxide (H2O2) by phorbol myristate acetate (PMA) stimulated rat peritoneal macrophages were studied. Macrophage-mediated ADCC, as measured by the lysis of 51Cr-labeled IgG-coated sheep red blood cells in an 18 h assay, was significantly enhanced in the presence of 100 ng/ml of PMA. Treatment of macrophage monolayers for 24 h with vincristine (10(-5)-10(-7) M), dexamethasone (10(-5)-10(-9) M) and adriamycin (10(-6) M) inhibited ADCC by PMA stimulated macrophages. Vincristine, dexamethasone and adriamycin also inhibited the secretion of O2- and H2O2 by PMA stimulated macrophages at similar concentrations that reduced the ADCC reaction. Methotrexate (10(-3)-10(-7) M) did not inhibit either ADCC or O2- and H2O2 secretion by PMA stimulated macrophages. These results suggest that select anticancer drugs can inhibit macrophage mediated cytotoxicity of antibody coated target cells by suppressing the release of reactive oxygen intermediates by activated macrophages.