IFN-gamma has been shown to decrease the susceptibility of target cells to NK cell-mediated cytotoxicity. In this report, the effect of IFN-gamma on the sensitivity of target cells to killing by various human lymphocyte cytotoxic activities such as NK/K, IL-2-augmented NK/K cell activity, and IL-2-activated killer activity were studied. Although NK-sensitive K562 cells showed marked resistance to NK cell activity as previously reported, the resistance was overwhelmed by augmentation of NK activity with IL-2. IL-2-activated killer cell activity, which can lyse NK-resistant tumor cell lines upon culture in IL-2, showed decreased cytotoxicity against most of the IFN-gamma-treated target cells tested. By contrast, no decrease of target cell sensitivity to K cells was observed, even though K cells were treated with IL-2. These findings suggest that as far as NK-resistant tumor cells are concerned, an IFN-dependent mechanism inhibits the Fc receptor-independent mediators of tumor surveillance, but not Fc receptor-dependent ones. This should be considered when planning adoptive immunotherapy of IL-2-activated killer cells for human malignancy.