Eight patients with treatment-resistant depression (TRD) underwent adjunctive chronic VNS for periods up to 14months. Although the patients denied dieting or change in activity level, there was a slow and highly significant loss of weight accompanied by decreased metabolism in the ventromedial prefrontal cortex, a cortical area involved in interoception with dense connections to the hypothalamus. The loss of weight was proportional to the initial weight. Weight loss was not related to change in depression scores. Neuromodulation through VNS may offer a novel approach to weight regulation.