Social rejection profoundly affects well-being. How do features of people's real-world social networks relate to responses to social exclusion? People central in social networks-e.g. who have many friends-may be less distressed by exclusion, since they have many sources of support, or more sensitive to it, if they are more attuned to social feedback. We characterized a village's social network; a subset of residents (N = 74) completed a functional magnetic resonance imaging (fMRI) study involving social exclusion in groups characterized by varying social relationships (spouses, friends, strangers). Highly-central individuals reported greater distress during exclusion by strangers, and their distress ratings scaled with responses in brain regions associated with social pain, negative affect, and mentalizing. Thus, while social connectedness is often considered a protective factor that promotes well-being, these findings suggest a potential ironic effect of social connectedness-vulnerability to distress in particular social contexts. This sensitization to exclusion could constitute an adaptive tendency to promote long-term wellness.