Abstract Up to two-thirds of patients diagnosed with major depressive disorder (MDD) will not respond to standard pharmacological and psychological interventions, suggesting a need to develop novel therapeutics. Decreased reactivity to positive stimuli, indexed by low amygdala reactivity to positive autobiographical memory recall, may be a causal mechanism interfering with recovery from MDD. Previous work suggests that individuals who do respond to antidepressant medications show increased amygdala activity to positive stimuli that is indistinguishable from controls, while those who do not respond fail to show this increase in amygdala activity. In several small studies we have shown that MDD participants are 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 the efficacy of this intervention in a large-scale confirmatory R01 clinical trial. N=200 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 receive yoked sham neurofeedback (instead of their own brain activity they see the signal from another participant who underwent amygdala rtfMRI-nf). We propose to use the same neurofeedback paradigm as our prior studies, with one critical difference. Rather than using a control condition that involves training another brain region, we will adopt a yoked sham control group in order to demonstrate that our findings are robust to the type of control condition used. We additionally aim to determine whether we can use self-report mechanisms to assess who might need the proposed neurofeedback intervention and whether they are likely to be successful in using it. Finally, we will work with implementation scientists to obtain feedback from end-users and clinicians to understand contextual influences on outcomes and increase intervention acceptability. Success will confirm a new non-pharmacological, non-invasive intervention for MDD individuals.