Social behavior is a defining mammalian feature that integrates emotional and motivational processes with external rewarding stimuli. It is thus an appropriate readout for complex behaviors, yet its neuronal and molecular bases remain poorly understood. In this study, we investigated the role of the mouse prefrontal area, particularly the involvement of β2-subunit nicotinic receptors (β2*-nAChRs) in a paradigm of social behavior with concurrent motivations. We previously observed that mice lacking β2*-nAChRs (β2(-/-)) display increased time in social contact and exaggerated approach movements toward the novel conspecific. Here, combining behavioral analysis, localized brain lesions, and lentiviral gene rescue, we found that c-Fos expression is specifically activated in the prelimbic (PrL) area of the prefrontal cortex (PFC) of mice exposed to a novel conspecific; lesions of the PrL area in wild-type mice produce the same social pattern as in β2(-/-) mice; and virally mediated reexpression of the β2-subunit in the PrL area of β2(-/-) mice rescues behavioral components in the social interaction task up to normal levels. Together, these data reveal that social interactions particularly mobilize the PrL area of the mouse PFC and that the presence of functional PrL β2*-nAChRs is necessary for this integrated behavior to emerge.