The present study evaluated short- and long-term efficacy and tolerability of augmentative vagus nerve stimulation (VNS) in a group of patients with treatment-resistant depression (N = 6). A statistically significant improvement in the Hamilton Depression Rating Scale (HDRS21) and Montgomery-Asberg Depression Rating Scale after 3 months (P = 0.039 and P = 0.05, respectively) was found in comparison with baseline (VNS implant). After 12 months, a statistically significant improvement was observed in the Hamilton Depression Rating Scale (HDRS21), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impression (P = 0.01, P = 0.005, and P = 0.001, respectively). Patients showed an overall favorable tolerability. Present data support VNS short- and long-term efficacy and tolerability in a small group of patients with treatment-resistant depression. Further controlled investigation is necessary to confirm the present open findings.