Objective: To compare quality-of-life (QOL) change associated with treatment as usual (TAU, any antidepressant treatment) versus adjunctive vagus nerve stimulation treatment (VNS + TAU) in a population of patients with treatment-resistant depression (TRD) for 5 years. Methods: Self-reported QOL assessments, using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), were gathered in a multicenter, longitudinal registry (January 2006- May 2015) comparing the antidepressant efficacy of VNS + TAU versus TAU in TRD. All depressed patients (N = 599), with either unipolar or bipolar depression, met DSM-IV-TR major depressive episode criteria and failed at least 4 adequate antidepressant trials. The Montgomery- Asberg Depression Rating Scale (MADRS) was administered by blinded raters. Q-LES-Q-SF scores in the treatment arms were compared via linear regression; linear regression was employed to compare QOL differences with percent decrease in MADRS. A subanalysis comparing Q-LES-Q-SF functional domain change was performed. Results: 328 VNS + TAU and 271 TAU patients with TRD were compared. On average, VNS + TAU demonstrated a significant, comparative QOL advantage over TAU (as demonstrated via nonoverlapping 95% confidence bands) that began at 3 months and was sustained through 5 years and was reinforced using a clinical global improvement measure. Patients receiving VNS + TAU, but not TAU alone, demonstrated a clinically meaningful QOL improvement (34% MADRS decrease) well below the classically defined antidepressant response (50% MADRS decrease). Exploratory post hoc subanalysis demonstrated that VNS + TAU had a significant advantage in multiple Q-LES-Q domains. Conclusion: Compared to TAU, adjunctive VNS significantly improved QOL in TRD, and this QOL advantage was sustained. Further, TRD patients treated with VNS experienced clinically meaningful QOL improvements even with depression symptom reduction less than the conventional 50% reduction used to ascribe "response.".