Objectives: Mycoplasmas are a group of eubacteria, which cause various diseases in animals and in humans, and can contribute to diseases produced by other infectious agents, particularly HIV. We have recently reported that intracerebral administration of Mycoplasma fermentans (MF) produces both neuroendocrine and behavioral alterations. Some of these responses were mediated by MF-induced production of prostaglandin E2 (PGE2). The aim of this study was to examine the role of glucocorticoids (GC) in regulating MF-induced brain prostaglandin production. Methods: Male rats were injected intracerebroventricularly with various doses of heat-inactivated MF, LPS or IL-1β and the following parameters were measured: (1) ex vivo production of hippocampal PGE2, (2) serum levels of ACTH and corticosterone, and (3) binding capacity of [3H]-dexamethasone (DEX) to hippocampal cytosol. Results: MF caused a small increase in hippocampal PGE2 production, but higher doses failed to produce a further increase. In contrast, the effects of LPS or IL-1β on PGE2 were dose-dependent. Removal of circulating GC by bilateral adrenalectomy significantly enhanced MF-induced brain PGE2 production. The three immune stimulators increased serum levels of ACTH and corticosterone to the same extent. Finally, MF, but not IL-1β increased the specific binding of [3H]-DEX to hippocampal cytosol. Conclusions: Brain PGE2 induced by MF is regulated by endogenous GC. These hormones have an attenuating effect on PGE2 production, probably through an MF-induced increase in GC binding by brain tissue. This mechanism may be important in the pathological effect of MF within the brain of AIDS patients.