Peripheral interleukin-1beta has been implicated in the initiation of fever responses, yet the pathways by which it influences brain function are still unclear. Sectioning the abdominal vagus has been reported to inhibit fever after intraperitoneal administration of interleukin-1beta, suggesting that vagal afferents participate in signaling the brain to mount a fever response to interleukin-1beta. However, the inhibitory effect of subdiaphragmatic vagotomy could be due to alterations in pharmacokinetics such that the intraperitoneally injected cytokine does not reach the general circulation in sufficient quantities to activate the brain via blood-borne signaling. We measured both fever and plasma levels of interleukin-1beta in vagotomized and sham-operated rats after intraperitoneal administration of 1 microg/kg human recombinant interleukin-1beta to determine whether vagotomy reduces fever and levels of circulating interleukin-1beta after intraperitoneal injection. Plasma levels of human recombinant and endogenous rat interleukin-1beta were measured in separate enzyme-linked immunosorbent assays. While intraperitoneal administration of human recombinant interleukin-1beta elevated plasma levels of this cytokine similarly in vagotomized and sham-operated animals, only sham-operated rats responded with fever. Plasma levels of endogenous rat interleukin-1beta were unchanged by any treatment. These results demonstrate that the blockade of intraperitoneal interleukin-1beta-induced fever after subdiaphragmatic vagotomy cannot be accounted for by alterations of interleukin-1beta levels in the general circulation.