Deep brain stimulation (DBS) of the nucleus accumbens alleviates anhedonia in treatment-resistant depression. Three patients with severe, treatment-resistant depression who had not responded to pharmacotherapy, psychotherapy, or electroconvulsive therapy (ECT) were implanted with bilateral DBS electrodes in the nucleus accumbens. Stimulation parameters were adjusted in a double-blind manner, and clinical ratings were assessed at each modification. Brain metabolism was also assessed before and after stimulation. Clinical ratings improved when the stimulator was on and worsened when it was off. No side effects were observed. FDG-PET scans showed significant changes in brain metabolism in fronto-striatal networks. These findings suggest that DBS to the nucleus accumbens may be a promising treatment for refractory depression. The nucleus accumbens is a key structure in the reward system, and dysfunction in this area is implicated in depression. DBS to this region may restore normal reward processing, as evidenced by the symptom of anhedonia. The study highlights the potential of DBS as a targeted treatment for depression, with immediate and significant clinical effects. No adverse effects were observed, and the results suggest that DBS can effectively alleviate depressive symptoms in treatment-resistant patients. The study also demonstrates that DBS can modulate brain metabolism in regions associated with reward and motivation, supporting the hypothesis that the nucleus accumbens is a critical target for treating depression. The findings indicate that DBS to the nucleus accumbens may offer a novel and effective approach for refractory depression.Deep brain stimulation (DBS) of the nucleus accumbens alleviates anhedonia in treatment-resistant depression. Three patients with severe, treatment-resistant depression who had not responded to pharmacotherapy, psychotherapy, or electroconvulsive therapy (ECT) were implanted with bilateral DBS electrodes in the nucleus accumbens. Stimulation parameters were adjusted in a double-blind manner, and clinical ratings were assessed at each modification. Brain metabolism was also assessed before and after stimulation. Clinical ratings improved when the stimulator was on and worsened when it was off. No side effects were observed. FDG-PET scans showed significant changes in brain metabolism in fronto-striatal networks. These findings suggest that DBS to the nucleus accumbens may be a promising treatment for refractory depression. The nucleus accumbens is a key structure in the reward system, and dysfunction in this area is implicated in depression. DBS to this region may restore normal reward processing, as evidenced by the symptom of anhedonia. The study highlights the potential of DBS as a targeted treatment for depression, with immediate and significant clinical effects. No adverse effects were observed, and the results suggest that DBS can effectively alleviate depressive symptoms in treatment-resistant patients. The study also demonstrates that DBS can modulate brain metabolism in regions associated with reward and motivation, supporting the hypothesis that the nucleus accumbens is a critical target for treating depression. The findings indicate that DBS to the nucleus accumbens may offer a novel and effective approach for refractory depression.