Prostaglandin (PG) E₂ produced in the periphery triggers the early phase of the febrile response to infection and may contribute to later phases. It can be hypothesized that peripherally synthesized PGE₂ transmits febrigenic signals to the brain via vagal afferent nerves. Before testing this hypothesis, we investigated whether the febrigenic effect of intravenously administered PGE₂ is mediated by the brain and is not the result of a direct action of PGE₂ on thermoeffectors. In anesthetized rats, intravenously injected PGE₂ (100 µg/kg) caused an increase in sympathetic discharge to interscapular brown adipose tissue (iBAT), as well as increases in iBAT thermogenesis, end-expired CO₂, and colonic temperature (T_c). All these effects were prevented by inhibition of neuronal function in the raphe region of the medulla oblongata using an intra-raphe microinjection of muscimol. We then asked whether the brain-mediated PGE₂ fever requires vagal signaling and answered this question by conducting two independent studies in rats. In a study in anesthetized rats, acute bilateral cervical vagotomy did not affect the effects of intravenously injected PGE₂ (100 µg/kg) on iBAT sympathetic discharge and T_c. In a study in conscious rats, administration of PGE₂ (280 µg/kg) via an indwelling jugular catheter caused tail skin vasoconstriction, tended to increase oxygen consumption, and increased T_c; none of these responses was affected by total truncal subdiaphragmatic vagotomy performed two weeks before the experiment. We conclude that the febrile response to circulating PGE₂ is mediated by the brain, but that it does not require vagal afferent signaling.