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This special supplement of the Journal of Adolescent Health combines 11 scientific articles and two commentaries highlighting PrEP implementation studies among Brazil and South Africa adolescents and youth. These articles highlight the unique HIV vulnerabilities and PrEP barriers experienced by youth in these countries and the implementation strategies required to address these barriers. Five articles are from PrEP1519, a prospective multisite open-label PrEP cohort study of adolescent men who have sex with men and transgender women ages 15 to 19 from three large capital cities in Brazil: Belo Horizonte, Salvador, and São Paulo. Six articles are from South Africa’s Project PrEP study, a demonstration project among adolescent girls and young women ages 15-24 that integrated PrEP provision as part of comprehensive HIV prevention services in primary health care settings in three provinces in South Africa.