There is a growing body of evidence suggesting that vagal afferents play a major role in peripheral-neural communication. This study was undertaken to determine whether a dose-dependent effect of lipopolysaccharide (LPS) on vagotomy-induced febrile unresponsiveness exists, and to examine the effect of vagotomy on LPS-induced increase in hypothalamic prostaglandin E2 (HT PGE2) production. Vagotomized and sham-operated rats were subjected to two experimental protocols. In the first, vagotomized and sham-operated rats were injected intraperitonealy with different doses of LPS (200, 500 and 1000 μg/kg) in order to examine the dose-dependent effect of LPS on the biphasic febrile response of the rats. In the second protocol, vagotomized and sham-operated rats were injected intraperitonealy with LPS (500 μg/kg). Two hours post injection, body temperature was measured, the rats were decapitated and blood was collected. Simultaneously, the rats' hypothalami were excised and incubated for 1 h in a Krebs-Henseleit buffer. Next, HT PGE2 was determined by radioimmunoassay. Vagotomy-induced gastric enlargement was then measured to examine the correlation between the magnitude of the enlargement and that of the vagotomy-related febrile unresponsiveness. It was found that vagotomized-induced febrile unresponsiveness is a dose-dependent effect. Subdiaphragmatic resection of the vagus prevented the biphasic febrile response caused by the lowest dose (200 μg/kg) of LPS, whereas the highest dose of LPS (1000 μg/kg) caused a similar biphasic febrile response in both vagotomized and sham-operated rats. Indeed, vagotomy attenuates LPS-induced increase in HT PGE2, and blocks the hypothermic phase of the febrile response. On the other hand, no correlation between gastric enlargement and febrile unresponsiveness was found. The results of the present study may cast further light on the crucial role of the vagus nerve as a peripheral-neural pathway in the mediation of the febrile response.