Previously, using fMRI, we demonstrated lower connectivity between right anterior superior temporal (ATL) and anterior subgenual cingulate (SCC) regions while patients with major depressive disorder (MDD) experience guilt. This neural signature was detected despite symptomatic remission which suggested a putative role in vulnerability. This randomised controlled double-blind parallel group clinical trial investigated whether patients with MDD are able to voluntarily modulate this neural signature. To this end, we developed a fMRI neurofeedback software (FRIEND), which measures ATL-SCC coupling and displays its levels in real time. Twenty-eight patients with remitted MDD were randomised to two groups, each receiving one session of fMRI neurofeedback whilst retrieving guilt and indignation/anger-related autobiographical memories. They were instructed to feel the emotion whilst trying to increase the level of a thermometer-like display on a screen. Active intervention group: The thermometer levels increased with increasing levels of ATL-SCC correlations in the guilt condition. Control intervention group: The thermometer levels decreased when correlation levels deviated from the previous baseline level in the guilt condition, thus reinforcing stable correlations. Both groups also received feedback during the indignation condition reinforcing stable correlations. We confirmed our predictions that patients in the active intervention group were indeed able to increase levels of ATL-SCC correlations for guilt vs. indignation and their self-esteem after training compared to before training and that this differed significantly from the control intervention group. These data provide proof-of-concept for a novel treatment target for MDD patients and are in keeping with the hypothesis that ATL-SCC connectivity plays a key role in self-worth. https://clinicaltrials.gov/ct2/show/results/NCT01920490.