Patients with treatment-resistant major depressive disorder (MDD) have limited options for addressing their symptoms that have not responded to antidepressant medications. Neuromodulation therapies such as TMS, VNS, and ECT have demonstrated efficacy, but each has features that limit their accessibility or acceptability. External combined occipital and trigeminal afferent stimulation (eCOT-AS) is a novel approach to non-invasive neuromodulation for depression. Proliv Rx, a wearable, home-use headset device by Neurolief, delivers electrical pulses through 3 output channels and 6 surface electrodes acting concomitantly on peripheral branches of both the occipital and trigeminal nerves. A randomized, double-blind, sham-controlled, multicenter study recently investigated the efficacy and safety of an 8 week-course of self-administered daily (30-40 min/session) active or sham eCOT-AS therapy in 124 adults with MDD who failed to respond to antidepressants. The double-blind phase was followed by an 8-week active open label phase. In this presentation, the positive trial results will be presented and differences between ProlivRx and other currently marketed home-use devices for depression will reviewed. Discussion of the findings will highlight the potential role and position of eCOT-AS relative to currently available treatment options for treatment-resistant MDD.