- Background Electroconvulsive therapy (ECT) is an effective alternative for pharmacotherapy in treatment-resistant depressive patients, but the side effects limit its use. Transcranial magnetic stimulation (TMS) has been proposed as a refined alternative, but most studies do not indicate that TMS is as effective as ECT for severe depression. Objective We propose that the limited effectiveness of standard TMS resides in its superficial effect on the cortex, although much of the pathophysiology of depression is associated with deeper and larger brain regions implicated in the reward system. Herein, we tested the effectiveness and safety of a novel TMS coil, the “H-coil,” which enables direct stimulation of deeper brain regions, at the expense of focality. Methods We have studied the antidepressant and cognitive effects induced by 4 weeks of high-frequency (20 Hz) repeated deep TMS (DTMS) over the prefrontal cortex (PFC) of 65 medication-free depressive patients, who have failed to benefit from prior medications. Patients were randomly assigned to various treatment configurations, differing in stimulation intensity and laterality. Effects were assessed by the 24-item Hamilton depression rating scale (HDRS-24) and several secondary outcome measures. Results A significant improvement in HDRS scores was found when high, but not low, stimulation intensity was used. Several cognitive improvements were evident, and no treatment-related serious adverse events were observed. Conclusions DTMS over the PFC was found safe and effective in alleviating depression. The results accentuate the significance of deep, high-intensity stimulation over low, and serve as the first study to indicate the potential of DTMS in psychiatric and neurologic disorders.