Complex and bidirectional relationships operate between the hypothalamic-pituitary-adrenal (HPA) axis and the immune system (IS) and either in vivo or in vitro evidence supports a physiological role of the HPA axis-IS network. A part of the well-known pharmacological effects of glucocorticoid hormones (GC) as immunodepressive agents, the direct effects of many HPA axis hormones on IS functions are actually documented also in physiologic conditions. Conversely, numerous IS soluble mediators are reported to affect the HPA axis functions at various steps of HPA axis regulation, in both physiologic and pathologic conditions. Stress and aging may represent two paradigmatic conditions to show the relevance of the bidirectional network between HPA axis and IS, as in both HPA activation and IS impairment are frequently coexistent. Finally, in the context of the wide spectrum of HIV-related HPA axis abnormalities, a case of a Cushing's syndrome associated to an acquired immunodeficiency syndrome (AIDS-related complex) in a 24-year-old homosexual drug abuser is reported.