This study tests the efficacy of Structural Ecosystems Therapy (SET), a family-ecological intervention, in improving psychosocial functioning when compared with an attention-comparison person-centered condition and a community control condition. A sample of 209 HIV-seropositive, urban, low-income, African American women was randomized into 1 of the 3 conditions. Results of growth curve analyses over 5 time points revealed that SET was more efficacious than either of the control conditions in reducing psychological distress and family-related hassles. However, contrary to hypotheses, SET was not more efficacious in increasing family support. Latent growth mixture modeling analyses indicated that SET was most efficacious for women who, on average, were at or near the clinical threshold for psychological distress and for women with high levels of family hassles. Implications for further intervention development are discussed.