This study had three aims: (1) to determine the relations between behavioral dysregulation, negative affectivity, and familial impairment with violence and suicidality (i.e., severity of ideation and attempts) in a sample of adolescent females with a psychoactive substance use disorder and controls; (2) to determine whether these relations are mediated by internalizing (depression/anxiety) and externalizing (nonviolent antisocial behavior) symptomatology; and (3) to determine whether severity of alcohol/drug use involvement moderates the relations between the mediating variables with violence and suicidality. Multiple behavioral, psychiatric interview, and self-report measures were used to index behavioral dysregulation, negative affectivity, familial impairment, internalizing and externalizing symptomatology, and violence and suicidality in one hundred sixty-one 14- to 18-year-old adolescent females with a psychoactive substance use disorder and in 80 controls. Structural equation modeling was used to determine the proposed relations. Results indicated that behavioral dysregulation, negative affectivity, and familial impairment were related to violence, whereas only familial impairment was related to suicidality. Internalizing symptomatology mediated the relation between familial impairment and suicidality, and was related to violence, whereas externalizing symptomatology mediated the relations between behavioral dysregulation, negative affectivity, and familial impairment with violence. Severity of alcohol/drug use involvement did not moderate the relations between internalizing or externalizing symptomatology with suicidality or violence. Nevertheless, the relation between internalizing symptomatology and suicidality was stronger in females with a greater degree of alcohol/drug use involvement, compared with those with a milder degree of involvement. Therefore, from a prevention standpoint, behavioral dysregulation, negative affectivity, familial impairment, as well as internalizing and externalizing symptoms, may serve as clinical "points of intervention" for altering the development of violence and suicidality in high risk and substance abusing youth.