Introduction: The CNS modulates inflammation in the gastrointestinal tract via efferent vagal pathways. We hypothesized that these vagal efferents receive synaptic input from vagal afferents, representing an autonomic feedback mechanism. The consequence of this vago-vagal reflex for afferent signal generation in response to LPS was examined in the present study. Methods: Different modifications of the vagal innervation or sham procedures were performed in anesthetized rats. Extracellular mesenteric afferent nerve discharge and systemic blood pressure were recorded in vivo before and after systemic administration of LPS (6 mgkg^-1 iv). Results: Mesenteric afferent nerve discharge increased dramatically following LPS which was unchanged when vagal efferent traffic was eliminated by acute vagotomy. In chronically vagotomized animals to eliminate both vagal afferent and efferent traffic, the increase in afferent firing 3.5 min after LPS was reduced to 3.2±2.5 impsec^-1 above baseline compared to 42.2±2.0 impsec^-1 in controls (p<0.001). A similar effect was observed following perivagal capsaicin to eliminate vagal afferent traffic only. LPS also caused a transient hypotension (< 10 min), a partial recovery and then persistent hypertension which was exacerbated by all 3 procedures. Mechanosensitivity was increased 15 minutes following LPS but had recovered 30 min in all subgroups except for chronic vagotomy. Conclusion: Discharge in capsaicin-sensitive mesenteric vagal afferents is augmented following systemic LPS. This activity through a vago-vagal pathway helps to attenuate the effects of septic shock. The persistent hypersensitivity to mechanical stimulation after chronic vagal denervation suggests that the vagus exerts a regulatory influence on spinal afferent sensitization following LPS.