Highly metastatic, in vivo-selected cells of RAW117-H10 large-cell lymphoma have been shown to be more resistant than poorly metastatic parental RAW117-P cells to the cytolytic and cytostatic activities of activated macrophages in co-culture experiments. Activated macrophages are known to produce soluble, cytostatic respiration-inhibiting factors, and such activities can be duplicated by interferon-gamma (IFN-gamma) or by combinations of IFN-gamma and Escherichia coli lipopolysaccharide (LPS). Highly metastatic RAW117-H10 cells are more resistant to the cytostatic effects of IFN-gamma and LPS than poorly metastatic RAW117-P cells, and short-term (up to 72 hr) treatment with IFN-gamma and LPS does not change the metastatic potentials of RAW117 cells. We have studied the effects of sequential selection of RAW117-P cells for increased resistance to IFN-gamma and LPS. After 7 to 13 sequential selections, the resulting variant lines were completely refractory to the growth-inhibitory effects of IFN-gamma and LPS and cross-tolerant to macrophage-conditioned medium. The selected variants also completely lost their experimental metastatic potentials and their tumorigenicities after s.c. or i.m. injection. Cytofluorographic analysis indicated reduced cell-surface expression of H-2Kd antigen and fibronectin receptor on the variant cells but no change in surface mu heavy-chain immunoglobulin. The IFN-gamma-selected lines were less adhesive to liver microvascular endothelial cells than the unselected RAW117 cell lines, but were equally sensitive to NK cytolysis by spleen cells. Our results suggest that exposure to certain cytokines can affect the growth and metastatic potential of RAW117 cells and result in the selection of resistant variants with altered biologic properties.