Recognition that the immune system may be important in regulating the clinical evolution of tumors and that corticosteroids suppress immune responses lends relevance to determining the concentrations in which sex hormones, currently used in the treatment of urologic malignancies exert immunosuppressive effects. We have investigated the effects of the sex hormones, diethylstilbestrol, diethylstilbestrol diphosphate, testosterone and progesterone, on in vitro lymphocyte blastogenesis as determined by 3H thymidine incorporation after stimulation with phytomitogens and alloantigens, and compared their effects to the effects of cortisol. Compared to cortisol these sex hormones are relatively weak suppressors of lymphocyte blastogenesis (cortisol 10(-7) M, progesterone 5 times 10(-6) M, testosterone 5 times 10(-5) M, diethylstilbestrol 5 times 10(-5) M and diethylstilbestrol diphosphate 10(-3) M) and probably are not significantly immunosuppressive in commonly used pharmacologic dosages. Similar results were observed with the T lymphocyte mitogens, phytohemagglutinin and concanavalin A, and in the combined T and B cell mitogen pokeweed. The fact that alloantigen-stimulated lymphocyte blastogenesis also was suppressed by diethylstilbestrol indicates that sex hormones exert their effects on the lymphocytes and not on the mitogens. Furthermore, sex hormones were not found to be cytotoxic to lymphocytes. It is postulated that the sex hormones tested act by suboptimal binding to glucocorticoid receptors in the lymphocytes and that the relative immunosuppressive potency of a given hormone is related to its affinity for the glucocorticoid receptor.