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In sub-Saharan Africa, nearly 90% of youth living with HIV acquired it from their mothers, but evidence lacks for health-related interventions for this population. We describe health-related interventions for youth living with perinatally acquired HIV in sub-Saharan Africa. A Preferred Reporting Items for Systematic Reviews (PRISMA) statement guided this review. We searched in PubMed, CINAHL, ProQuest, PsychINFO, Science Direct, Embase, and Scopus databases for peer-reviewed articles addressing health-related interventions for youth living with perinatally acquired HIV in sub-Saharan Africa. Of the 4,139 articles, 11 met the inclusion criteria. We identified eight interventions targeting HIV prevention and care, ART adherence, disclosure, behavioral health, cognitive and academic function, sexual, reproductive, psychosocial, and physical health. Most of the interventions targeted psychosocial health. No intervention was holistic. Findings were diverse regarding intervention effectiveness. Providers need to devise interventions that combine behavioral, biomedical, and structural services to meet this population's complex health care needs. [ABSTRACT FROM AUTHOR]