The CA125 tumor marker is an antigenic determinant present on a high-molecular-weight glycoprotein expressed by more than 80% of newly diagnosed nonmucinous epithelial ovarian cancers. OVCA 433 human ovarian carcinoma cells express the CA125 marker at the cell surface and release large quantities of this antigen into culture medium. Here we show that release of CA125 by OVCA 433 cells is 90 to 95% inhibited by treatment with 1 x 10(-7) M dexamethasone, as determined using a biotin-based enzyme-linked immunosorbent assay utilizing OC125 monoclonal antibodies to CA125. The relative cell surface density of CA125 is also decreased following dexamethasone treatment as determined by immunofluorescence techniques using OC125 monoclonal antibodies. Inhibition of CA125 expression is specific for glucocorticoids, such as cortisol and dexamethasone, and does not occur with estrogens, progestins, androgens, or mineralocorticoids. CA125 inhibition is also dependent on the concentration of steroid used, with half-maximal and maximal inhibition by dexamethasone occurring at about 3 x 10(-9) M and 1 x 10(-7) M, respectively. Previous work has shown that OVCA 433 cells are growth inhibited by glucocorticoids and contain 14,000 glucocorticoid receptors per cell with an affinity for dexamethasone (Kd = 6.6 x 10(-9) M) which corresponds well with the concentration required for half-maximal CA125 inhibition. This correspondence, together with the specificity of CA125 inhibition for glucocorticoids, suggests that this effect is mediated by glucocorticoid receptors and is a specific biological effect of glucocorticoids on this cell type. Our results demonstrate glucocorticoid inhibition of CA125 expression by ovarian carcinoma cells and suggest that endogenous or therapeutically administered glucocorticoids can influence CA125 production by tumors in vivo.