The purpose of this study was to examine a model of factors that place psychiatrically hospitalized girls at risk for non-suicidal self-injury (NSSI). The role of familial and peer interpersonal difficulties, as well as emotional dysregulation, were examined in relationship to NSSI behaviors. Participants were 99 adolescent girls (83.2% Caucasian; M age = 16.08) admitted to a psychiatric hospital. Structural equation modeling indicated the primacy of emotional dysregulation as an underlying process placing adolescents at risk for NSSI and mediating the influence of interpersonal problems through the family and peer domains. When family and peer relationships were characterized by conflict and lack of support for managing emotions, adolescents reported more dysregulated emotion processes. Family relational problems were directly and indirectly related to NSSI through emotional dysregulation. The indirect processes of peer relational problems, through emotional dysregulation, were significantly associated with NSSI frequency and severity. The findings suggest that the process by which interpersonal difficulties contribute to NSSI is complex, and is at least partially dependent on the nature of the interpersonal problems and emotion processes.