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Abstract Background Youth living with HIV (YLHIV) in Sub-Saharan African (SSA) are less likely to adhere to antiretroviral therapy (ART) and other health-related regimens. As a consequence, YLHIV are not only at risk for health problems and mental health comorbidities, but are also at risk for cognitive deficits, including in areas of memory and executive functioning. The Suubi+Adherence study followed 702 adolescents (10-16 years of age) receiving bolstered standard of care and a family economic empowerment intervention comprising an incentivized youth financial savings account (YSA) augmented with financial literacy training (FLT) and peer mentorship. The study findings pointed to superior short-term viral suppression and positive adolescent health and mental health functioning among participants receiving the intervention. The original group of adolescents who received Suubi+Adherence are now transitioning into young adulthood. This paper presents a protocol for the follow-up phase titled Suubi+Adherence Round 2. Methods The original cohort in Suubi+Adherence will be tracked for an additional five years (2020-2025). Specifically, the long term follow-up will allow to: 1) ascertain the extent to which the short term outcomes identified in the first 6 years of the intervention are maintained as the same group transitions through young adulthood; and 2) address new scientific questions regarding ART adherence; HIV care engagement; protective health behaviors; and the potential of FEE to mitigate the development of HIV-associated neurocognitive disorders in YLHIV. Additionally, the team examines the potential mechanisms through which the observed long-term outcomes happen. Moreover, the Suubi+Adherence-Round 2 adds a qualitative component and extends the cost effectiveness component. Discussion Guided by asset and human development theories, Suubi+Adherence-R2 will build on the recently concluded Suubi+Adherence study to conduct one of the largest and longest running studies of YLHIV in SSA as they transition into young adulthood. The study will address new scientific questions regarding long-term ART adherence, HIV care engagement, protective health behaviors, and the potential of FEE to mitigate the development of HIV-associated neurocognitive disorders in YLHIV. The findings may inform efforts to improve HIV care among Uganda’s YLHIV, with potential replicability in other low-resource countries. Trial registration ClinicalTrials.gov , ID: NCT01790373