Abstract: Because of the well-known role of the thymus in the regulation of immune function, we investigated whether the lack of thymus may affect hypothalamo-pituitary-adrenal (HPA) axis activity. Eight-week-old female Swiss nude (athymic) and BALB/c (normal) mice were used to study (a) the “in vivo” response of the HPA axis to various stresses and stimuli acting at either hypothalamic, pituitary, or adrenal levels and (b) the in vitro response of pituitary and adrenal cells to CRH and ACTH stimulation, respectively. The results indicate that (1) basal plasma ACTH levels were significantly (p < 0.05) higher in Swiss nude than in BALB/c mice, whereas basal corticosterone (B) levels were similar in both strains of mice; (2) the stress-induced release of ACTH and B in plasma was significantly (p < 0.05) lower in Swiss nude than in BALB/c mice, regardless of the stimulus applied; (3) the “in vitro” pituitary response to CRH and the adrenal response to ACTH were significantly (p < 0.05) lower in Swiss nude than in BALB/c mice; and (4) whereas hypothalamic CRH and pituitary ACTH contents were similar in both strains, adrenal B content was significantly (p < 0.05) lower in athymic mice. Immune reconstitution of the athymic nude mice by injecting splenocytes obtained from syngeneic heterozygous (i.e., immunologically fully competent) donors produced a significant increase in the B adrenal content of the nude mice. Among the splenocytes, CD4+ T-lymphocytes play a particularly important role in the release of ACTH from cells of the immune system. In conclusion, our results indicate that athymic nude mice have a blunted HPA axis response to various stresses and stimuli; this defect seems to reside at both the pituitary and adrenal levels. Immune reconstitution of the nude mice leads to a normalization of the adrenal B content.