Vagus Nerve Stimulation (VNS) is an alternative treatment for medically or surgically refractory epilepsy. For about one third of the treated patients, the amount of seizures is reduced with more than 50%. However, the working mechanism of VNS is still not fully understood. Therefore it is currently impossible to predict the patient’s response to the treatment. Research on the mechanism of action is needed to find biomarkers indicating a positive response on the therapy. The anti-epileptic effect of VNS is linked to the norepinephrine level in the brain, which modulates the P300 component of the event-related potential. This potential can be measured using the auditory oddball paradigm. In this research we explore whether and how EEG source reconstruction of this component can help to identify a biomarker for the efficacy of VNS therapy. When we compare responders vs. non-responders, we find significant differences in brain activity in the left hippocampus, fusiform gyrus and insular lobe, indicating a possible biomarker for the efficacy of VNS. When comparing the two conditions: VNS turned off vs. VNS turned on, we find indications that the limbic system is involved in the mechanism of action of VNS.