Background Growing research on transgender youth is accounting for the variety of ways in which young people define their genders and sexualities. Because of this growing representation, more research is needed to understand how intersectional identities and stigma affect risk for HIV acquisition along the HIV care continuum and engagement in mental and physical health care. Little is known about accessibility to HIV-related prevention services of nonbinary and transmasculine youth, and further understanding of the impacts on transfeminine people—those who have historically faced the highest prevalence of HIV positivity—is crucial. Objective The overarching aims of the Trans Youth of Color Study are to conduct longitudinal research with a cohort of transgender minority youth (TGMY), explore factors that aid in the prevention of new HIV infection and transmission, and reduce HIV- and AIDS-related disparities by focusing on successful engagement in care. Findings from this research will be used to inform the development of new interventions designed to engage TGMY in the HIV prevention and care continua. Methods Longitudinal research (baseline and follow-up assessments every 6 months for 3 waves of data collection) followed a cohort (N=108) of transgender youth of color recruited in Los Angeles, California, United States. Participants were recruited using multiple community-informed strategies, such as from local venues, social media, and participant referral. In addition to self-report surveys, urine was collected to assess recent use of illicit drugs, and blood, rectal, and throat swabs were collected to test for current sexually transmitted infection and HIV infection. Additional blood and plasma samples (10 mL for 4 aliquots and 1 pellet) were collected and stored for future research. Results Participants in the Trans Youth of Color Study were recruited between May 25, 2018, and December 7, 2018. Baseline and longitudinal data are being analyzed as of August 2022. Conclusions The findings from this research will inform adaptations to existing evidence-based HIV prevention interventions and help to guide new interventions designed to engage TGMY, especially those who are Black, Indigenous, or people of color, in the HIV prevention and care continua. International Registered Report Identifier (IRRID) DERR1-10.2196/39207

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