Treatment-resistant major depression (TRMD, major depressive disorder that fails to respond to numerous therapies) is a relatively common and clinically challenging disorder. In many cases, the most severely affected TRMD patients have received surgical intervention (subcaudate tractotomy, limbic leucotomy, anterior capsulotomy, and anterior cingulotomy). New treatments, including vagus nerve stimulation (VNS) and deep brain stimulation, have emerged to treat individuals with TRMD. We describe the case of a woman, 53 years of age, with a long and sustained history of TRMD (33 years), which was unresponsive to numerous treatments (multiple pharmacotherapies, psychotherapy, electroconvulsive therapy [ECT]). Additionally, her TRMD failed to respond to a bilateral anterior cingulotomy. She underwent placement of a cervical vagus nerve stimulator and a brief course of ECT (3 unilateral treatments). Her depression improved markedly, and it has remained in sustained remission for 3.5 years. This case suggests a potential synergistic effect of VNS and ECT, as well as provides possible clues to the neural circuitry of VNS in TRMD.