Adrenocortical secretory responses to chemical mediators and ACTH in CD1 ICR nu/nu (athymic) mice were compared with those in CD1 ICR (normal) mice. The bilateral adrenals of normal or athymic mice were perfused in situ with artificial medium equilibrated by 95% O2 + 5% CO2. Infusion of serotonin induced the secretory response of corticosterone significantly at 10 nM and markedly at 100 nM and the response at 1000 or 10000 nM declined as compared with that at 100nM in normal mice. Total corticosterone secretion in response to 100 or 1000 nM serotonin in athymic mice was about one fourth that in normal mice, respectively. Corticosterone responses to ACTH at the range of 10 to 300 pg/ml in athymic mice were comparable to those in normal mice. Infusion of histamine, platelet activating factor(PAF), or compound 48/80 did not induce significant corticosterone response in both normal and athymic mice. The data suggest that the congenital defect of the thymus and/or hair causes the hyporesponsiveness of adrenocortical cells to serotonin although the adrenal cortex of athymic mice is able to perform its function in response to ACTH.