Exposure of rat thymus cells to glucocorticoids leads to a decreased ability of nuclei to survive the lysis of whole cells by hypotonic shock. In this study, a similar glucocorticoid-induced increase in "nuclear fragility" was found in both corticoid-sensitive and -resistant lines of P1798 mouse lymphosarcoma cells. In corticoid-sensitive cells a small increase in nuclear fragility is seen after a 2-hr exposure to cortisol (10(-6) M); by 3 hr it is 20 to 40% above control values. This effect appears to be a specific glucocorticoid response. Both cortisol and dexamethasone at 10(-7) M produce an effect, 10(-6) M testosterone is inactive, and cortexolone, which binds to glucocorticoid receptors, reduces the effect. Cycloheximide, at concentrations that inhibit protein synthesis, also blocks this effect. While the corticoid-resistant line also demonstrates an effect of similar magnitude, it requires a much longer exposure to the hormone (6 hr). Distinct differences in the "hardiness" of the two cell lines (nuclei of the corticoid-resistant line are less fragile) measurable in the absence of hormones appears to account for the differential susceptibility to steroids. On this basis a new theory of resistance is advanced where the emergence of resistance is related to structural differences in the cells.