PROJECT SUMMARY Transgender men who have sex with men (trans MSM) are at-risk of HIV acquisition in the US and require gender-affirming culturally responsive biobehavioral HIV prevention strategies. The goal of the proposed study is to assess the ability of digitally delivered peer-based strategies to improve PrEP uptake in PrEP-indicated HIV-negative adult trans MSM (defined behaviorally as sex with a person who has a penis). This study proposes a digital open-label randomized 2x2 factorial trial (1:1:1:1 randomization) of peer-delivered HIV prevention strategies designed to increase PrEP uptake in trans MSM residing in high HIV incidence geographic hotspots in the Eastern and Southern US. The specific aims are to: (1) Compare the efficacy of individual (PrEP4T: one-on-one peer navigation) and group-based (LifeSkills for Men: small group-based behavioral intervention) peer-delivered HIV prevention strategies implemented over 6 mo to increase PrEP uptake (primary outcome) in 300 PrEP-indicated HIV-negative adult trans MSM; (2) Examine mechanisms by which peer-delivered interventions impact PrEP uptake focusing on healthcare empowerment, trans community support, and information, motivation, and behavioral skills; and (3) Explore PrEP decision-making and intervention experiences qualitatively. Biobehavioral assessments will be conducted every 3 mo for 21 mo with self-administered surveys; remote HIV self-testing (4th gen tests) and biologic measures of PrEP via emtricitabine triphosphate (FTC-TP) and tenofovir diphosphate (TFV-DP) using dried blood spots (DBS) to evaluate uptake of approved TFV-based PrEP regimens in this population; and STIs (gonorrhea, chlamydia, syphilis) via electronic medical record (EMR) releases. The team will use a participatory population perspective to work “with” not “on” trans MSM ensuring meaningful participation of trans MSM. The proposed study is significant by addressing HIV prevention in an underserved NIH health disparities population and will fill critical gaps in biobehavioral HIV prevention and peer-engaged approaches. The study is aligned with US national priorities to implement integrated strategies for HIV prevention in at-risk populations in high HIV incidence geographic hotspots and will advance the 2021-2025 National Strategic Plan to End the HIV epidemic.