BackgroundAdolescent alcohol and drug use (ADU) is a significant public health challenge. Uganda, one of the poorest countries in Sub-Saharan Africa (SSA), has the second-highest rate of per capita alcohol consumption in SSA, and over one-third of Ugandan adolescents have used alcohol in their lifetime (over 50% of them engage in heavy episodic drinking). These estimates further increase in fishing villages, a key HIV-vulnerable population, where ADU is normative. However, few studies have assessed ADU among adolescents and youths living with HIV despite their increased risk for ADU and its impact on engagement in HIV care. Moreover, data on risk and resilience factors for ADU are scarce as only few studies evaluating ADU interventions in SSA have reported positive outcomes. The majority have been implemented in school settings, potentially excluding adolescents in fishing communities with high school dropout rates, and none have targeted risk factors including poverty and mental health, which are rampant among adolescents and youths living with HIV and their families, undermine their coping skills and resources, and have been associated with increased risk for ADU among them.ObjectiveWe propose a mixed methods study with a sample of 200 adolescents and youths living with HIV (aged 18-24 years) seen at 6 HIV clinics in southwestern Uganda’s fishing communities to (1) examine the prevalence and consequences of ADU and identify the multilevel risk and resilience factors associated with ADU among them and (2) explore the feasibility and short-term effects of an economic empowerment intervention on ADU among them.MethodsThis study comprises four components: (1) focus group discussions (FGDs) with adolescents and youths living with HIV (n=20) and in-depth qualitative interviews with health providers (n=10) from 2 randomly selected clinics; (2) a cross-sectional survey with 200 adolescents and youths living with HIV; (3) a randomized controlled trial with a subgroup of adolescents and youths living with HIV (n=100); and (4) 2 postintervention FGD with adolescents and youths living with HIV (n=10 per group).ResultsParticipant recruitment for the first qualitative phase has completed. As of May 4, 2023, ten health providers from 6 clinics have been recruited, provided written consent to participate, and participated in in-depth qualitative interviews. Two FGDs was conducted with 20 adolescents and youths living with HIV from 2 clinics. Data transcription, translation, and analysis of qualitative data has commenced. The cross-sectional survey will commence shortly after and dissemination of the main study findings is targeted for 2024.ConclusionsOur findings will advance our understanding of ADU among adolescents and youths living with HIV and inform the design of future interventions to address ADU among them.Trial RegistrationClinicalTrials.gov NCT05597865; https://clinicaltrials.gov/ct2/show/NCT05597865International Registered Report Identifier (IRRID)PRR1-10.2196/46486