OBJECTIVES Electroconvulsive therapy (ECT) is a mainstay in both acute and long-term management of difficult-to-treat depression. However, frequent acute courses of ECT or prolonged maintenance ECT treatment may increase adverse-effect burden and/or reduce patient acceptability. Therefore, we investigated the effectiveness of adjunctive vagus nerve stimulation (VNS) therapy as an alternative strategy for long-term maintenance treatment in ECT-responsive patients. METHODS This retrospective chart review identified maintenance ECT patients with unipolar (n = 5) and bipolar depression (n = 5) from 2 large hospital systems who had a history of ECT response, but the patients had significant residual incapacitating symptoms or increasing concerns regarding the burden associated with ECT and opted to receive adjunctive VNS therapy. The patients were followed for 2 years after VNS implantation. Response and remission were defined as Clinical Global Impression-Severity scale scores of ≤2 and 1, respectively, obtained at 1- and 2-year postimplantation compared with just before VNS implantation. RESULTS One-year postimplantation, 6 of 10 had responded of which 5 met remission criteria. All 10 patients benefited from adjunctive VNS therapy with either fewer hospitalizations and/or ECT sessions. Seven of 10 stopped maintenance ECT by the end of year 1; an additional patient stopped maintenance ECT by year 2. No patients required an acute course of ECT during the 2-year follow-up. There was a statistically significant reduction (P < 0.0001) in mean (SD) Clinical Global Impression-Severity scale scores between baseline (5.4 [0.51]) and the 1-year postimplantation (2.1 [1.37]) time points, and between baseline and the 2-year postimplantation (2.3 [1.16]) time points, whereas no difference existed between the 1- and 2-year postimplantation time points. CONCLUSIONS Vagus nerve stimulation therapy may be a useful maintenance strategy in patients with difficult-to-treat depression receiving maintenance ECT.