PURPOSE: The aim of this study is to expand the current knowledge on the relationship between poverty, family functioning, and the mental health of adolescent girls in families affected by poverty and HIV/AIDS in southern Uganda. The study investigates the association between family functioning and mental health and examines whether family functioning moderates the intervention effect on adolescent mental health. METHODS: Longitudinal data were collected over the course of 24 months in a cluster randomized controlled trial conducted among N=1,260 girls aged 14-17 years in Uganda. Participants were randomized into control group (n=408 girls from n=16 schools), matched youth development accounts treatment, YDA (n=471 girls from n=16 schools), and integrated intervention combining YDA with multiple family group component (n=381 girls from n=15 schools). RESULTS: We found a significant positive association between family functioning and mental health of adolescent girls in our sample. Moderator analyses suggests that effect of the intervention on Beck Hopelessness Scale was significantly moderated by family cohesion (χ2 (4) =21.43; p = .000), frequency of family communication (χ2 (4) =9.65; p = .047), and quality of child-caregiver relationship (χ2 (4) =11.12; p = .025). Additionally, the intervention effect on depression was moderated by the comfort of family communication (χ2 (4) =10.2; p = .037). DISCUSSION: The study findings highlight the importance of family functioning when examining the link from poverty to adolescent mental health. The study contributes to the scarce evidence suggesting that asset-accumulation opportunities combined with a family strengthening component may improve parenting practices and adolescent mental health in poor households.