The stress-vulnerability model of addiction relapse states that the impact of life stress on alcohol and other drug use is influenced by several types of psychosocial risk and protective factors. Coping skills have been shown to be protective against alcohol or other drug use in adolescents and adults. To date, the influence of life stress and coping on addiction relapse has not been investigated among substance use disordered youth with comorbid Axis I psychopathology. In the present study, 80 adolescents, ages 13 to 17, were followed six months after treatment for substance use and Axis I disorders. Participants completed measures of psychopathology, substance use, life stressors and coping during treatment and at three and six months following treatment. Coping ability best predicted youth substance use at six months. Negative life events moderated the relation between coping and frequency of substance use. These results suggest that coping is a protective factor for return to substance involvement post-treatment, particularly for comorbid youth who have experienced high levels of life stress.