It has recently been shown that subdiaphragmatic vagotomy blocks some of the effects of inflammatory stimuli on brain-controlled functions. Therefore, vagal afferent fibers have been proposed to play a prominent role in the communication pathways between the immune system and the brain. In the present study, we investigated the effect of subdiaphragmatic vagotomy on fever induced by intraperitoneal or intramuscular injection of lipopolysaccharide (LPS) or muramyl dipeptide (MDP), which are both cytokine-inducing agents in guinea pigs. Intraperitoneal and intramuscular injections of LPS or MDP were tested in the same animal with an interval of 1 wk. In one experiment, intraperitoneal injections of LPS or MDP were performed at the beginning, followed by intramuscular injections 1 wk later. In another experiment, intramuscular injections of LPS or MDP were performed at the beginning, followed by intraperitoneal injections 1 wk later. The febrile response to intraperitoneal injection of LPS was almost completely abrogated in vagotomized animals compared with sham-operated controls (from 30-330 min after intraperitoneal injection of LPS). The suppression of LPS fever was quantitatively the same in both experiments. In contrast, the response to intramuscular injection of LPS was the same in vagotomized and sham-operated guinea pigs in each of the experiments. Fever induced by intraperitoneal injection of MDP was partly attenuated by subdiaphragmatic vagotomy (between 150 and 300 min after intraperitoneal injection of MDP) in both experiments. Again, the febrile response to intramuscular injections of MDP was not significantly altered by subdiaphragmatic vagotomy. In conclusion, the suppressive effect of subdiaphragmatic vagotomy on fever induced by peripheral immune stimuli depends on the route of pyrogen administration. Because the febrile response to intraperitoneal injection of bacterial pyrogens is strongly diminished in vagotomized guinea pigs, it is suggested that vagal afferent fibers play a crucial role in the transduction of immune signals from the abdominal cavity to the brain.