Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are common in HIV infection. To characterize further the site of these derangements and their possible causes, eight male drug addicts with symptomatic HIV infection (stage IV C2) underwent the following investigations: repeated baseline determinations of cortisol, adrenocorticotropin (ACTH), interleukin 1 beta (IL-1 beta), IL-6 and interferon alpha (IFN-alpha); and ovine corticotropin-releasing hormone (CRH) test (100 micrograms IV) for ACTH and cortisol determinations. Baseline cortisol levels were either normal or elevated in all patients. A significant linear correlation was found between baseline levels of cortisol and both IL-6 (r = 0.955; p < 0.001) and IL-1 beta (r = 0.863; p < 0.005), but not between cortisol and ACTH or between ACTH and circulating cytokines. Both ACTH and cortisol responses to CRH were nearly absent in six out of eight patients, and delayed in the others. The areas under the curves of both ACTH and cortisol after CRH were significantly lower in HIV patients than in a group of eight healthy control subjects (p = 0.0157 for ACTH and p = 0.046 for cortisol). Out data suggest the possibility of an inappropriate stimulation of the HPA axis in symptomatic HIV infection by HIV-induced release of cytokines, with a blunted pituitary and adrenal response to CRH.