Glucocorticoids inhibit various components of the acute phase response, particularly the increase in body temperature (fever) induced by a variety of stimuli. In the present study these observations have been extended, and we have determined the effect of glucocorticoid treatment or surgical adrenalectomy on the cytokine and prostaglandin (PG) concentrations in plasma and cerebrospinal fluid (CSF) during the febrile response to endotoxin. Dexamethasone treatment, either before or after endotoxin injection, markedly inhibited fever and the increased plasma interleukin (IL)-6 and CSF IL-6, PGE2, and PGF2 alpha concentrations. Adrenalectomized (ADX) rats showed higher fevers and plasma and CSF IL-6, PGE2, and PGF2 alpha, concentrations compared with sham-operated animals and exhibited a lower plasma-to-CSF IL-6 ratio than sham-operated animals. Dexamethasone pretreatment also inhibited fever induced by centrally injected TNF-alpha, IL-1 beta, or IL-6. Pyrogenic response to IL-8 was not modified by indomethacin but was markedly inhibited by prior treatment with dexamethasone. These results support the hypothesis that endogenous glucocorticoids function as part of an inhibitory feedback system involved in the modulation of fever and that multiple mechanisms may be involved in their antipyretic effect.