AIM The purpose of this study was to evaluate the efficacy of vagus nerve stimulation (VNS) as a therapeutic option for treatment-resistant depression (TRD), with follow-up periods of 1, 3 and 5 years after VNS surgery. METHODS We examined 27 consecutive patients with unipolar TRD. Depressive symptoms were evaluated both at baseline and at follow-up after the surgery by means of the 21-item Hamilton Rating Scale for Depression (HAM-D 21). RESULTS The mean HAM-D preoperative score was 25.6. Twenty-two patients were evaluated after 1 year of treatment, and the mean improvement of the HAM-D score was of 10.3. Five patients (20%) went into complete remission (HAM-D < 7) after 1 year, six patients (22.3%) were considered responders (50% reduction of HAM-D scoring) and eight patients had score reduction of less then 20%. Nineteen patients were evaluated after 24–36 months: the average improvement on the HAM-D score was of 12.1 points (47.2%). One patient went into complete remission and eight patients (42.1%) were responders. Up to the present date, seven patients have undergone re-evaluation at 48–60 months from surgery showing an average score reduction of 14.2. Two more patients obtained complete remission, while four of them did not have any improvement since their last follow-up control visit. CONCLUSION VNS antidepressant was successful in 20% of TRD patients, although some patients required several months to obtain clinical improvement or remission of symptomatology. Nonetheless this procedure can be considered as a useful option in treating TRD.