Abstract Up to two-thirds of patients diagnosed with major depressive disorder (MDD) will not respond to standard pharmacological and psychological interventions and will be considered treatment resistant (TR-MDD). Decreased reactivity to positive stimuli, indexed by low amygdala reactivity to positive autobiographical memory recall, may be a causal mechanism interfering with recovery from TR-MDD. Previous work in our lab suggests that individuals who do respond to antidepressant medications show increased amygdala activity that is indistinguishable from controls relative to baseline, while TR-MDD individuals fail to show this increase in amygdala activity. Furthermore, we have found that MDD participants (more generally, not specifically TR- MDD) are indeed able to increase their amygdala response during positive memory recall via real-time fMRI neurofeedback (rtfMRI-nf) training, and that this increase is associated with large and rapid reductions in depressive symptoms. Here, we propose to evaluate whether rtfMRI-nf training to increase the amygdala response to positive memories may serve as an intervention for TR-MDD. The R61 period will involve intervention refinement and evaluation of mechanism; N=40 TR-MDD individuals will undergo five amygdala rtfMRI-nf training sessions and we will assess changes in amygdala activity with the goal of confirming that patients with TR-MDD are able to increase the amygdala response to positive memories, and to determine the minimal number of training sessions required for sufficient target engagement/amygdala asymptote to be reached. The R33 phase will involve a mechanistic comparison to a control intervention and evaluation of clinical change (including duration of effects). N=60 TR-MDD individuals will be randomly assigned under double-blind conditions to the amygdala rtfMRI-nf intervention or to a control rtfMRI-nf intervention where they are trained to regulate a parietal region putatively not involved in emotional processing or MDD. Success will suggest a new non-pharmacological, non-invasive intervention for a traditionally treatment-resistant population of MDD individuals.