Background The rapid scale-up of HIV therapy across Africa has failed to adequately engage adolescents living with HIV (ALWHIV). Retention and viral suppression for this group (ALWHIV) is 50% lower than for adults. Indeed, on the African continent, HIV remains the single leading cause of mortality among adolescents. Strategies tailored to the unqiue developmental and social vulnerabilities of this group are urgently needed to enhance successful treatment. Methods We carried out a five-year longitudinal cluster randomized trial (ClinicalTrials.gov ID: NCT01790373) with adolescents living with HIV (ALWHIV) ages 10 to 16 years clustered at health care clinics to test the effect of a family economic empowerment (EE) intervention on viral suppression in five districuts in Uganda. In total, 39 accredited health care clinics from study districts with existing procedures tailored to adolescent adherence were eligible to participate in the trial. We used data from 288 youth with detectable HIV viral loads (VL) at baseline (158 –intervention group from 20 clinics, 130 –non-intervention group from 19 clinics). The primary end point was undetectable plasma HIV RNA levels, defined as > 40 copies/ ml. We used Kaplan-Meier (KM) analysis and Cox proportional hazard models to estimate intervention effects. Findings The Kaplan-Meier (KM) analysis indicated that an incidence of undetectable VL (0.254) was significantly higher in the intervention condition compared to 0.173 (in non-intervention arm) translated into incidence rate ratio of 1.468 (CI: 1.064–2.038), p = 0.008. Cox regression results showed that along with the family-based EE intervention (adj. HR = 1.446, CI: 1.073–1.949, p = 0.015), higher number of medications per day had significant positive effects on the viral suppression (adj.HR = 1.852, CI: 1.275–2.690, p = 0.001). Interpretation A family economic empowerment intervention improved treatment success for ALWHIV in Uganda. Analyses of cost effectiveness and scalability are needed to advance incorporation of this intervention into routine practice in low and middle-income countries.