There is increasing evidence that cytokines contribute to the immunopathogenesis of human immunodeficiency virus (HIV) infection. It may be, therefore, that compensatory rises in circulating cytokine antagonists also occur in HIV infection and that such changes mark disease progression. To test this idea, plasma concentrations of the cytokine antagonists Ormelanocyte-stimulating hormone (α-MSH), interleukin-1 receptor antagonist (Il-lra), and soluble tumor necrosis factor receptor (sTNFr) were measured in patients of different Centers for Disease Control (CDC) categories of HTV infection and in seronegative controls. Plasma levels of all these cytokine antagonists were higher in HIV-infected patients. Hl-ra and sTNFr concentrations were correlated with indicators of disease activity: positively with plasma neopterin and negatively with CD4+ T lymphocyte counts. α-MSH and sTNF r were greater in CDC groups III and IV, whereras IL-lra was elevated only in the latter group. Because cytokines activate the hypothalamic-pituitary-adrenal axis and adrenal steroids inhibit cytokine production, we measured circulating adrenocorticotropic hormone (ACTH) and Cortisol in HIV-infected patients and investigated relations among these hormones, cytokine antagonists, and markers of disease progression. It appears that these physiological modulators of cytokine activity are not closely linked to sTNFr, IL-lra and α-MSH: there were no significant correlations between plasma concentrations of ACTH or Cortisol and those of cytokine antagonists, nor were there correlations between hormones and markers of disease progression such as neopterin or CD4+ T cell counts. It is notable that severe adrenal insufficiency was extremely rare (3%) in HIV-infected patients; it was confined to the AIDS group and was consistently secondary to ACTH deficiency. Finally, because of the recent expansion of the AIDS case definition to include all patients with CD4+ T cell counts less than 200/μl, we examined cytokine antagonists, hormones and neopterin in a subset of patients included in the AIDS group because of low CD4+ T cells in the absence of clinical criteria formerly required for AIDS case definition. Cytokine antagonists and neopterin concentrations in patients with low CD4+ T cells were similar to those of patients with the clinical complications of AIDS. The results indicate that: (1) plasma concentrations of cytokine antagonists are increased in HIV infection particularly in later stages of the disease, and (2) the recent expansion of the AIDS case definition to one including a low CD4+ T cell count results in the inclusion of patients who have disease markers similar to those of patients who meet the clinical criteria for AIDS.