1. The actions of peripheral corticotrophin-releasing factor-41 (CRF-41) on the febrile responses of conscious rabbits induced by peripherally administered polyinosinic.polycytidylic acid (poly(I).poly(C)) have been studied using a CRF-41 receptor antagonist (alpha-helical CRF(9-41) and anti-CRF-41 monoclonal antibodies. 2. Temperature responses were monitored continuously using rectal thermistor probes. Test substances were administered intravenously (i.v.), or for central CRF-41 antagonism experiments, via an indwelling third ventricle cannula (I.C.V.). Blood samples were taken at time intervals from a marginal ear vein and plasma cortisol levels determined by radioimmunoassay. 3. Poly(I).poly(C) (2.5 micrograms/kg) stimulated a reproducible biphasic rise in body temperature with a lag phase of 45-60 min and peaks at 90 and 225 min. 4. The febrile response to poly(I).poly(C) (2.5 micrograms/kg I.V.) was antagonized by blockade of peripheral CRF-41 actions using either monoclonal anti-CRF-41 antibodies (2.5 mg/kg i.v.) or the CRF-41 receptor antagonist (alpha-helical CRF(9-41); 25 micrograms/kg i.v.) administered 5 min prior to the pyrogen. 5. Centrally administered CRF-41 receptor antagonist (2.5 micrograms/kg I.C.V.) failed to affect the febrile response to poly(I).poly(C) (2.5 micrograms/kg i.v.). 6. CRF-41 immunoneutralization after the onset of temperature rises caused an immediate and significant defervescence. 7. In conclusion, these results suggest a modulatory pro-pyretic role for endogenous peripheral CRF-41 in the febrile responses to poly(I).poly(C).