The ability of both exogenous and endogenous glucocorticoids (GCs) to inhibit proinflammatory cytokine production was investigated in vivo. Specifically, we investigated the effects of elevated GC levels on interleukin (IL)-1-induced release of IL-6 into both blood and cerebrospinal fluid (CSF). Three experiments were conducted in rhesus macaques to elevate corticoid levels for at least 4 h before administration of IL-1. The first study used dexamethasone pretreatment, the second utilized ACTH to stimulate endogenous cortisol release, while the third relied on a psychological challenge to stimulate the hypothalamic-pituitary-adrenal axis. Contrary to our a priori predictions, none of these treatments attenuated the IL-1-induced release of IL-6 into CSF. Additionally, the pattern in the blood response was similar, such that the IL-6 response was not blocked, although there was a trend toward a reduction of this response. These data indicated that the IL-1-induced IL-6 response is for the most part resistant to corticosteroid influence, such that even when a partial inhibition was sometimes evident in blood, cytokine release in the central nervous system was not affected.