Early threat exposure is a transdiagnostic risk factor for psychopathology, and evidence suggests that genetic variation in the oxytocin receptor (OXTR) moderates this association. However, it is unclear if this gene-by-environment (G×E) interaction is tied to unique risk for disorder-specific outcomes or instead increases shared risk for general psychopathology. Moreover, little is known about how this G×E interaction increases risk. The current study utilized a prospective, longitudinal sample of females (n = 2,020) to examine: (a) whether the interaction between early threat exposure and OXTR variation (rs53576, rs2254298) confers risk for disorder-specific outcomes (depression, anxiety, borderline and antisocial personality disorders) and/or general psychopathology in early adulthood; and (b) whether social–emotional deficits (emotion dysregulation, callousness, attachment quality) during adolescence constitute mediating mechanisms. Consistent with hypotheses, the interactive effects of early threat exposure and OXTR variation (rs53576) predicted general psychopathology, with threat-exposed women carrying at least one copy of the rs53576 A-allele at greatest risk. This interaction was mediated via emotional dysregulation in adolescence, with threat-exposed A-allele carriers demonstrating greater emotion dysregulation, and greater emotion dysregulation predicting general psychopathology in early adulthood. Findings suggest that this G×E places women at risk for a broad range of psychopathology via effects on emotion dysregulation.