Norepinephrine (NE) microdialyzed into the preoptic area (POA) raises core temperature (Tc) via 1-adrenoceptors (AR), quickly and independently of POA prostaglandin (PG)E2, and 2-AR, after a delay and PGE2-dependently. Since systemic lipopolysaccharide (LPS) activates the central noradrenergic system, we investigated whether preoptic NE mediates LPS fever. We injected LPS (2 µg/kg iv) into guinea pigs prepared with intraPOA microdialysis probes and determined POA cerebrospinal (CSF) NE levels. We similarly microdialyzed prazosin (1 blocker, 1 µg/µl), yohimbine (2 blocker, 1 µg/µl), SC-560 (cyclooxygenase [COX]-1 blocker, 5 µg/µl), acetaminophen (presumptive COX-1v blocker, 5 µg/µl), or MK-0663 (COX-2 blocker, 0.5 µg/µl) into other animals before iv LPS and measured CSF PGE2. All the agents were perfused at 2 µg/min for 6 h. Tc was monitored constantly. POA NE peaked within 30 min after LPS, then returned to baseline over the next 90 min. Tc increased within 12 min to a first peak at ~60 min and to a second at ~150 min, then declined over the following 2.5 h. POA PGE2 followed a concurrent course. Prazosin pretreatment eliminated the first Tc rise, but not the second; PGE2 rose normally. Yohimbine pretreatment did not affect the first Tc rise, which continued unchanged for 6 h; the second rise, however, was absent and PGE2 levels did not increase. SC-560 and acetaminophen did not alter the LPS-induced PGE2 and Tc rises; MK-0663 prevented both the late PGE2 and Tc rises. These results confirm that POA NE is pivotal in the development of LPS fever.