We investigated whether the weak febrile response to pyrogens in newborns is due to a diminished activation of the putative pyrogen mediator, prostaglandin (PG)E2. Indwelling cannulas in the third ventricle of lambs (age, 5-31 days) and adult ewes were used to collect cerebrospinal fluid (CSF) for radioimmunoassay of PGE2. Intravenous (i.v.) endotoxin caused a smaller increase in body temperature but a larger increase in CSF PGE2 in lambs compared to adults. PGE2 by intracarotid infusion raised body temperature in 5 of 7 trials in 3 lambs and in 4 of 4 trials in 1 adult. Endotoxin given intracerebroventricularly (i.c.v.) induced a rise in temperature and CSF PGE2 in the lamb but, in the adult, these responses were delayed and smaller. Interleukin-1 i.c.v. and PGE2 i.c.v. were weak pyretic agents at both ages. We conclude that the lamb's diminished febrile response to endotoxin i.v. is not caused by a lesser rise in CSF PGE2, rather it may be due, at least in part, to reduced responsiveness to this putative mediator. Regardless of age, the sheep differs from other species in that pyrogen/PGE2 coupling occurs primarily at a site in brain that is better accessible from blood than CSF.