Social anxiety disorder (SAD) is characterized by aberrant prefrontal activity during reappraisal, an adaptive cognitive approach aimed at downregulating the automatic response evoked by a negative event. Cognitive behavioral therapy (CBT) is first-line psychotherapy for SAD, however, many remain symptomatic after treatment indicating baseline individual differences in neurofunctional activity may factor into CBT outcome. An emotion regulation strategy practiced in CBT is cognitive restructuring, a proxy for reappraisal. Therefore, neural response during reappraisal may serve as a brain-based predictor of CBT success. Prior to 12 weeks of individual CBT, 34 patients with SAD completed a validated emotion regulation task during fMRI. Task instructions included ‘Reappraise,’ that is, use a cognitive approach to reduce affective state to a negative image, which was contrasted with looking at a negative image (‘Look’). Regression results for Reappraise (vs. Look) revealed greater reduction in symptom severity was predicted by less pre-CBT activation in the dorsolateral prefrontal cortex (DLPFC). Regarding predictive validity, DLPFC significantly classified responder status. Post-hoc analysis revealed DLPFC activity, but not demographic data, baseline clinical measures, or reappraisal-related affective state during fMRI, significantly accounted for the variance in symptom reduction. Findings indicate patients with SAD are more likely to benefit from CBT if there is less pre-treatment DLPFC recruitment, a region strongly implicated in emotion regulation. Patients with reduced baseline frontal activation when reappraising negative stimuli may be especially helped by explicit cognitive interventions. Further research is necessary to establish DLPFC as a stable brain-based marker of treatment outcome.