- Background: Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder induced by traumatic experiences. To date, psychotherapy and drug treatment achieve only partial success, indicating need for further development of treatment strategies. Recent research has found that impaired acquired fear extinction capability serves as an important factor at the pathogenesis of the disorder. Medial prefrontal cortex (mPFC) hypo-activity has been implicated in this extinction impairment, providing insight as to why some trauma exposed individuals will develop PTSD. Objective: To test whether fear extinction can be facilitated and therapeutic effect achieved by repeated mPFC deep transcranial magnetic stimulation (DTMS) of PTSD patients resistant to standard treatment. Methods: In a double-blind study, 30 PTSD patients were enrolled and randomly assigned into 3 treatment groups: A) DTMS after brief exposure to the traumatic event with the script-driven imagery procedure; B) DTMS after brief exposure to a non-traumatic event; C) sham stimulation after brief exposure to the traumatic event. Results: Significant improvement was demonstrated in the intrusive component of the CAPS scale in patients administered DTMS after exposure to the traumatic event script, while patients in the control groups showed no significant improvement. Similar trend was demonstrated in the Total-CAPS score as in the other rating scales. A significant reduction in the HR response to the traumatic script was evident in group A, further supporting the above results. Conclusions: Combining brief script-driven exposure with DTMS can induce therapeutic effects in PTSD patients. A wide multi-center study is suggested to substantiate these findings. Trial registration: ClinicalTrials.gov identifier: NCT00517400.