Abstract: For this study, functional magnetic resonance imaging was used to examine whether medial prefrontal cortex (MPFC) activity during self-knowledge reference reflects the uniqueness of self-knowledge. Experiment 1 investigated neural activity during self-knowledge reference (“Does the word describe you?”) and self-monitoring (“Does the word make you feel pleasant?”). The results showed that self-knowledge reference and self-monitoring activate common neural substrates within the MPFC. Experiment 2 compared neural activity produced by self-knowledge reference, other-knowledge (acquaintance-knowledge) reference (“Does this word describe the person?”), and evaluation (“Is this word socially desirable?”). Results showed no increase in MPFC activity during self-knowledge reference relative to other-knowledge reference. Furthermore, self-knowledge reference and other-knowledge reference share common neural substrates within the MPFC. The results described indicate that it is unlikely that MPFC activity during self-knowledge reference reflects the uniqueness of self-knowledge. The feature, as reflected in MPFC activity, is discussed.