Administration of dehydroepiandrosterone (DHEA) to female rats produces a condition of reproductive failure and ovarian cysts similar to that seen in women having polycystic ovarian disease. On the other hand, DHEA may have beneficial effects on the immune system. We sought to determine the effect of DHEA, when administered in pharmacological amounts, on the thymus and spleen of prepubertal (25 day old) and young adult (60 day old) female rats. Since the adrenal, by means of its production of corticosteroids, also is known to modulate the immune system, we also evaluated the effects of DHEA administration on this gland. The daily SC administration of DHEA (6 mg/100g BW) to young adult female rats led to progressive and striking reductions in thymic weights (greater than 85% suppression after 20 days compared to vehicle treated animals). There were no effects of DHEA on body weights or the weights of the spleen. DHEA treatment also led to significantly reduced weights of the adrenals , which was sustained at about 15-20% below normal over 5-20 days treatment. Ovariectomy of the rats 5 days before initiation of DHEA or vehicle treatment gave rise to significant increases in thymic and spleenic weights in control animals and strikingly blunted the inhibitory effects of DHEA treatment for 10 days on the thymus; DHEA had no effect on the ovariectomy-induced rise in the weight of the spleen. Ovariectomy also had no effect on the inhibitory effects of DHEA on adrenal weight. Similar, albeit quantitatively less striking, responses were noted to occur after DHEA treatment in immature female rats. These data indicate that DHEA in doses sufficient to interfere with ovarian cyclicity also has potentially adverse effects on the adrenal and thymus. The ovary appears to play an independent role in maintenance of the size of the thymus and spleen and also may mediate some of the effects of DHEA on the thymus but not those on the adrenals.