IFN-gamma has been shown to reduce the sensitivity of tumor cells to lysis by NK cells. The close relationship between NK cells and lymphokine-activated killer (LAK) cells has prompted us to investigate whether IFN-gamma pre-treatment also affects the sensitivity of tumor cells to lysis by LAK. We have shown previously that IFN-gamma can induce a significant reduction in the sensitivity of both cultured and fresh (surgically obtained) human tumor cells to lysis by LAK. Herein we show that changes in the sensitivity to LAK lysis of cultured human tumor cells can be induced by as little as 1 to 10 U/ml of IFN-gamma; a dose well within the range that can be achieved in vivo. Protection is induced within hours after treatment with IFN-gamma and is dependent on the continued presence of IFN-gamma. Tumor cells cultured in IFN-gamma for several days remain less sensitive to lysis and do not become refractory to IFN-gamma-mediated protection. In the absence of IFN-gamma, treated tumor cells regain "normal" sensitivity to lysis within 48 to 72 h. We have also investigated the mechanisms by which IFN-gamma reduces tumor cell sensitivity to LAK lysis using cold target competition, monolayer depletion, direct binding, and kinetic assays. IFN-gamma pre-treatment does not alter the kinetics of tumor cell lysis by LAK. Our data are most compatible with a model in which IFN-gamma reduces the ability of a subpopulation of tumor cells to induce the LAK effector cell to initiate lysis. These results are closely parallel to observations made on the IFN-mediated protection of targets from NK lysis and support the notion that NK- and LAK-mediated lysis are closely related. These results may have significance in vivo because high levels of IFN-gamma may be present at the tumor site or may be induced after therapeutic immunomodulation.