Efforts were directed to achieve an increased lymphokine-activated non-MHC-restricted killing (LAK) activity greater than that induced by rIL-2 alone. Human peripheral blood (PB) and bone marrow (BM)-derived mononuclear cells (MC) were exposed in vitro to multiple cytokine combinations, including rIL-6, rIL-7, rIFN-alpha and rIFN-gamma in the presence of either suboptimal or optimal doses of rIL-2. Our results have shown that BMMC are a potential source for induction of increased LAK activity upon exposure to multiple cytokine combinations, whereas PBMC could not be successfully stimulated under the same conditions. Fifty-five to 62% of BM-derived samples stimulated with high dose rIL-2 + rIL-7 or rIL-2 + rIL-7 + rIL-6 + rIFN-gamma exhibited a higher degree of cytotoxicity than BM samples stimulated with rIL-2 alone. Exposure of PB-derived large granular lymphocytes (LGL) to various cytokine combinations led to increased proliferation after stimulation with suboptimal dose of rIL-2 in the presence of rIL-6 and rIL-7. This increase was not observed in induction of cytotoxicity. We suggest that BMMC activated by multiple cytokine combinations could play an active role in improving antitumor response in vivo by contributing to the control of minimal residual tumor cell growth, particularly post-BM transplantation.