This report examines the effect of Structural Ecosystems Therapy (SET) for (n=143) HIV+ African American women on rate of relapse to substance use relative to both a person-centered approach (PCA) to therapy and a community control (CC) group. A prior report has shown SET to decrease psychological distress and family hassles relative to these two comparison groups. In new analyses, SET and CC had a significant protective effect against relapse as compared to PCA. There is evidence that SET’s protective effect on relapse was related to reductions in family hassles, whereas there was not a direct impact of change in psychological distress on rates of relapse. Lower retention in PCA, perhaps caused by the lack of a directive component to PCA may have put these women at greater risk for relapse. Whereas SET did not specifically address substance abuse, SET indirectly protected at-risk women from relapse through reductions in family hassles.