Reappraisal, a cognitive approach intended to alter an emotional response, is generally associated with prefrontal cortical recruitment and decreased limbic activity. However, the extent to which neurofunctional activity predicts successful reappraisal is unclear. During fMRI, 60 healthy participants completed a reappraisal paradigm, which included reappraising negative images to reduce emotional reactivity (‘ReappNeg’) and viewing negative images and experiencing the negative affect they evoke (‘LookNeg’). After each trial, participants rated their emotional response on a Likert-type scale where higher values indicated more negative affect. Reappraisal ability was based on a difference value (ΔReappNeg-LookNeg) such that negative values signified successful reappraisal (‘SR’; n = 38) and positive values, unsuccessful reappraisal (‘USR’; n = 22). Neural activity based on ReappNeg-LookNeg conditions from 37 regions of interest encompassing cortical and limbic areas was submitted to Principal Component Analysis (PCA). Resulting PCA factors were submitted to discriminant function analysis to evaluate which factor(s) predicted SR and USR groups. Results showed a factor with high loadings for certain frontal areas (e.g., left dorsomedial prefrontal cortex) and limbic regions (e.g., bilateral amygdala) predicted 71.1% of cases in the SR group and 68.2% of cases in the USR group. Additionally, successful reappraisal corresponded with more activation in the factor with high loadings for frontal areas and less activity in the factor associated with limbic regions. Results are consistent with studies of individual differences where more prefrontal engagement and less limbic activity is associated with effectual reappraisal, but for the first time, a neural ‘signature’ for successful reappraisal has been demonstrated.