Objective: Vagus nerve stimulation (VNS) is a novel therapy in resistant epilepsy, and is undergoing clinical trials in resistant depression. The mechanism of action of VNS is assumed to be due to modulation of deep brain structures via its afferent connections. As the vagus nerve has potentially important immunological actions that may have relevance to its therapeutic effects, we hypothesised that an additional mechanism may occur via vagally mediated actions on cytokine synthesis. Methods: Patients (n = 10) with resistant depression were studied in the weeks prior to, and 3 months following, implantation of a vagus nerve stimulator. No medication changes were made during the course of the study. High-sensitivity ELISA kits were used to measure plasma IL-1β, IL-6, TNF-α, IL-10 and TGF-β concentrations. C-reactive protein (CRP) was measured using a high sensitivity immunonephelometry assay. Results: There were highly significant increases in the plasma levels of IL-6, TNF-α and TGF-β. Increases seen with IL-10 and IL-1β were not significant. Plasma CRP levels were unchanged. Conclusion: VNS is associated with marked peripheral increases in pro- and anti-inflammatory circulating cytokines. Such changes are unlikely to be non-specific inflammatory reactions, reflected by CRP levels. In view of gathering evidence supporting a role for the immune system in modulating affect, as well as seizure activity, these effects of VNS may be therapeutically relevant.