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Guilt and shame are usually evoked during interpersonal interactions. However, no study has compared guilt and shame processing under such circumstances. In the present study, we investigated guilt and shame in an interpersonal context using functional magnetic resonance imaging (fMRI). Behaviorally, participants reported more “guilt” when their wrong advice caused a confederate's economic loss, whereas they reported more “shame” when their wrong advice were correctly refused by the confederate. The fMRI results showed that both guilt and shame activated regions related to the integration of theory of mind and self-referential information (dorsal medial prefrontal cortex, dmPFC) and to the emotional processing (anterior insula). Guilt relative to shame activated regions linked with theory of mind (supramarginal gyrus and temporo-parietal junction) and cognitive control (orbitofrontal cortex/ventrolateral prefrontal cortex and dorsolateral prefrontal cortex). Shame relative to guilt revealed no significant results. Using multivariate pattern analysis, we demonstrated that in addition to the regions found in the univariate activation analysis, the ventral anterior cingulate cortex and dmPFC could also distinguish guilt and shame. These results do not only echo previous studies of guilt and shame using recall and imagination paradigms but also provide new insights into the psychological and neural mechanisms of guilt and shame.