P1798 murine lymphoma cells die when exposed to glucocortioids in vivo. Such cells are sensitive to glucocorticoids in culture in serum-free medium, and 80–90% of wild type cells will die within 24 h after addition of 0.1 µm dexamethasone. However, addition of fetal bovine serum prevents cell death in culture. Variants that were selected for resistance to the cytolytic effects of glucocorticoids in vivo are relatively insensitive to dexamethasone in culture. Insensitive variants die more slowly than wild type cells, with 10–20% cell death observed within 24 h after addition of dexamethasone. Conditioned medium from insensitive cultures protects wild type P1798 cells from dexamethasone in serum-free medium. Such medium contains one or more factors that attenuate the lytic response. This lysis resistance factor(s) has the properties of a protein and may be a growth factor. Expression of the lysis resistance factor(s) appears to be regulated by glucocorticoids. These studies define an heretofore uncharacterized mechanism whereby the ability of malignant lymphoid cells to elaborate and/or respond to an autocrine factor(s) influences the extent to which such cells die when exposed to glucocorticoids in culture and probably in vivo.