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Objective: In controlled treatment trials, 40%–60% of unmedicated depressed individuals respond to cognitive behavior therapy (CBT). The authors examined whether pretreatment neural reactivity to emotional stimuli accounted for this variation. Method: Unmedicated depressed individuals (N=14) and never depressed comparison subjects (N=21) underwent fMRI during performance of a task sensitive to sustained emotional information processing. Afterward, depressed participants completed 16 sessions of CBT. Results: Participants whose sustained reactivity to emotional stimuli was low in the subgenual cingulate cortex (Brodmann’s area 25) and high in the amygdala displayed the strongest improvement with CBT. Conclusions: The presence of emotion regulation disruptions, which are targeted in CBT, may be the key to recovery with this intervention.