Background: Functional neuroimaging studies have suggested activation of midline frontoparietal brain regions to be at the core of self-related processes. However, although some studies reported involvement of the insula, little attention has been paid to this region as forming part of the "self''-network. Methodology/Principal Findings: Using functional magnetic resonance imaging (fMRI), we aimed at replicating and extending previous studies by scanning subjects whilst reflecting upon their own personal qualities as compared to those of an acquaintance. A third condition with statements about general knowledge was used to control for attention, semantic processing and decision making processes. The results showed a significant effect of task in brain activity, consistent with previous findings, by which both person conditions recruited a common set of medial prefrontal and posterior regions, yet significant differences between self and other were found in the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC). Notably, significant neural activation in the left anterior insula was observed as uniquely associated with self-reflection. Conclusions/Significance: The results provide further evidence for the specific recruitment of anterior MPFC and ACC regions for self-related processing, and highlight a role for the insula in self-reflection. As the insula is closely connected with ascending internal body signals, this may indicate that the accumulation of changes in affective states that might be implied in self-processing may contribute to our sense of self
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