Objectives. To investigate the long-term impacts of a family economic intervention on physical, mental, and sexual health of adolescents orphaned by AIDS in Uganda.Methods. Students in grades 5 and 6 from 48 primary schools in Uganda were randomly assigned at the school level (cluster randomization) to 1 of 3 conditions: (1) control (n = 487; 16 schools), (2) Bridges (1:1 savings match rate; n = 396; 16 schools), or (3) Bridges PLUS (2:1 savings match rate; n = 500; 16 schools).Results. At 24 months, compared with participants in the control condition, Bridges and Bridges PLUS participants reported higher physical health scores, lower depressive symptoms, and higher self-concept and self-efficacy. During the same period, Bridges participants reported lower sexual risk-taking intentions compared with the other 2 study conditions. At 48 months, Bridges and Bridges PLUS participants reported better self-rated health, higher savings, and lower food insecurity. During the same period, Bridges PLUS participants reported reduced hopelessness, and greater self-concept and self-efficacy. At 24 and 48 months, Bridges PLUS participants reported higher savings than Bridges participants.Conclusions. Economic interventions targeting families raising adolescents orphaned by AIDS can contribute to long-term positive health and overall well-being of these families.Trial Registration. ClinicalTrials.gov registration no. NCT01447615.