Vagus nerve stimulation (VNS) for treatment of drug-resistant epileptic seizures has been reported to have additional positive mood effects as obtained by psychiatric ratings. To avoid rater bias effects, this study used self-report questionnaires and examined changes in self-reported mood and health-related quality of life following 6 months of VNS treatment. From 40 adult patients treated with VNS since the beginning of the study, 28 patients (mean age: 35.4 years) with unchanged medication were included. Repeated-measures MANOVA revealed a significant general mood improvement. Post hoc univariate tests obtained improvements of tenseness and dysphoria but not of depression, level of activity, or health-related quality of life. Mood and seizure outcome were correlated. VNS may improve unspecific states of indisposition and dysphoria. Absolute seizure reduction contributes to this antidysphoric effect. Since baseline depression scores were low, findings do not contradict but complement earlier reports of an antidepressive effect of VNS.