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Vasopressin, a key molecular regulator of social behavior, is implicated in promoting self-protective responses to threats against physical safety and resources. However, its role in defending against self-view threats-common in social interactions and critical to well-being-remains unclear. This study investigates the neural mechanisms through which vasopressin modulates self-protective responses to spontaneous social comparison. In a double-blind, placebo-controlled neuroimaging study, 48 healthy male participants were randomized to receive intranasal vasopressin or placebo. Participants then underwent fMRI while rating their satisfaction with social evaluations and monetary outcomes assigned to a stranger, friend, or themselves. Compared to placebo, vasopressin selectively intensified contrastive emotional responses to social evaluations of the stranger, decreasing satisfaction with positive evaluations and increasing satisfaction with negative evaluations, relative to those of the self or friend. At the neural level, vasopressin reduced the neural distinction between the stranger and the self/friend in medial prefrontal cortex (mPFC), an effect that was stronger in more socially dominant individuals. Complementing this regional effect, vasopressin attenuated whole-brain multivariate differentiation and reduced functional connectivity from ventral mPFC to the temporoparietal junction and precuneus. Together, these converging neuroimaging findings suggest that vasopressin may increase the psychological salience of strangers and thereby modulate their neural representations, potentially engaging self-protective affective processes. Our findings elucidate novel neuropsychological mechanisms through which vasopressin amplifies emotional defense against social threats and offer insights into potential clinical applications for psychiatric conditions characterized by impaired self-protection.