The pyrogenic interferon inducer polyinosinic:polycytidylic acid (Poly I:C) was shown to stimulate rises in both prostaglandin E2 (PGE2) and prostaglandin F(2α) (PGF(2α)) in conscious rabbits in vivo. Poly I:C (2.5 μg/kg) stimulated a fivefold rise in circulating immunoreactive (ir) PGE2, with a lag phase of 60 min, which was sustained during the subsequent 4-h period of observation. Poly I:C also stimulated a 2.5-fold rise in circulating irPGF(2α) with a lag phase of 90 min, which was followed by a return to basal levels after 5 h. The rises in circulating irPGE2 and irPGF(2α) stimulated by Poly I:C were prevented by pretreatment with the non-steroidal anti-inflammatory drug ketoprofen. Both the irPGE2 and irPGF(2α) responses to Poly I:C (2.5 μg/kg, i.v.) were antagonized by the corticotrophin-releasing factor-41 (CRF-41) receptor antagonist (α-helieal CRF (9-41), 25 μg/kg, i.v.) administered 5 min prior to the pyrogen. Peripheral immunoneutralization using an anti-CRF-41 monoclonal antibody (KCHMB001, 2.5 mg/kg, i.v.) administered 5 min prior to the pyrogen, also inhibited both the PGE2 and PGF(2α) responses to Poly I:C (2.5 μg/kg, i.v.). However, control mouse IgG also inhibited the PGE2 response. In conclusion, these results suggest a modulatory role for endogenous peripheral CRF-41 in the circulating prostaglandin responses to the pyrogen Poly I:C and this effect may be responsible for the antipyretic actions of peripherally administered CRF-41 antagonists and antibodies.