It is unclear whether the involvement of the medial prefrontal cortex (mPFC) during encoding is restricted to the evaluative processing of to-be-encoded stimuli or if it is instead actively engaged during memory formation. The difficulty of assessing the contribution of the mPFC to encoding based on previous neuroimaging studies partly arises from the use of several types of stimuli, such as emotional or social ones. These different types of stimulus content could differently modulate mPFC activity during memory formation and thus partly explain the variable contribution of this region to encoding. Using emotional/neutral and social/nonsocial pictures, we conducted an event-related functional magnetic resonance imaging study using a subsequent memory paradigm as the main analytical strategy. We observed that the brain activity in the dorsal and orbital mPFC is significantly and specifically predictive of the successful encoding of social compared with nonsocial pictures. In contrast, the activity in the amygdala specifically predicts the successful encoding of emotional compared with neutral pictures. The modulation of the mPFC by social information in a memory encoding context could be associated with the initiation of self-referential processes whose contribution is to enhance memory formation.