Rejection sensitivity (RS) is a cognitive-affective processing disposition, whereby individuals anxiously expect, readily perceive, and overreact to rejection, and is believed to emerge in response to interpersonal rejection in childhood. Maladaptive responses to rejection might subsequently contribute to depression. A single nucleotide polymorphism on the OXTR gene (rs53576) may provide a biological basis for RS given that individuals with a mutation on the OXTR gene often display social deficits. In the current study, in the presence of the OXTR gene mutation on both alleles (AA), individuals who experienced had interpersonal trauma displayed greater RS than in the absence of the mutation (GG/AG). Moreover, perceived social support buffered the relationship between RS and depression, whereas unsupportive social interaction exacerbated the relationship. Taken together, this study sheds light on the cognitive-affective responses related to RS, and understanding some of the dynamic biological and psychosocial processes that contribute to mental health outcomes.