The ability of protease inhibitors to modulate NK and ADCC cell activities was studied. NK and ADCC cell activities were suppressed by 1,10 phenanthroline (PHE), N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), L-1-tosylamide-2-phenylethylchoromethyl ketone (TPCK), N-benzoyl-DL-tyrosine ethyl ester (BTEE), and phenylethylchoromethyl fluoride (PMSF). The effect of these protease inhibitors on ADCC was not mediated through the early phase of cytotoxicity involving Fc-receptor binding, since they failed to alter EoxA rosetting of effector cells. The results suggest that an activated esterase system might play a role in the later phase of the cytotoxic mechanism by ADCC cells and perhaps NK cells.