Background. Young transgender women (YTW) have the highest HIV prevalence/incidence than any other risk group in the U.S. The repeated exposure to gender minority stigma compounded by the psychosocial challenges associated with social disadvantage and economic marginalization exacerbates disparities in HIV incidence and invalidates YTW’s gender identity. This can lead to behaviors (e.g., substance use, sex work, healthcare avoidance) that potentiate HIV acquisition risk. In order to decrease HIV incidence among YTW, an intervention needs to 1) address HIV risk as part of YTW’s life contexts; 2) be accessible and far-reaching such that the entire at-risk population can participate (e.g., rural areas) during a time most convenient for them; and 3) be highly sustainable with low associated costs to implement in real-world settings. Preliminary Research. The current proposal is a culmination of over 10 years of research with this population, which included: 1) developing and pilot testing an empowerment-based, group-delivered (in person) HIV prevention intervention for YTW ages 16-29, called Project LifeSkills; 2) conducting a full-scale, multisite randomized controlled trial (RCT) of Project LifeSkills (NIMH R01; MPIs: Garofalo/Mimiaga), where we demonstrated the efficacy of this intervention to reduce HIV risk (note: Project LifeSkills is currently the only “best evidence” HIV risk reduction intervention for YTW included among the CDC’s compendium of evidence-based interventions); 3) adapting the face-to-face version of Project LifeSkills to an online-delivered, mobile app platform (containing 4 online modules) via an NIMH-funded R56 (MPIs: Kuhns, Mimiaga), called “LifeSkills Mobile”; and 4) completing an iterative usability pilot trial of the LifeSkills Mobile app to enhance participant acceptability/feasibility of study procedures and conducted exit interviews to evaluate the app’s look, feel, and functional components. Conceptual Model. LifeSkills Mobile is an mHealth intervention to promote biobehavioral HIV prevention strategies based on empowerment theory and was developed using a community-based participatory research approach. Overview of Study Design. We propose to conduct an RCT to assess the efficacy of the LifeSkills Mobile intervention in comparison to a standard of care (SOC) condition among 5,000 YTW recruited online. The primary outcome is reduction in incident HIV infections; a secondary outcome is total condomless anal/ vaginal sex acts occurring in the context of insufficient PrEP protection. At baseline and every 6 months through 48 months, enrolled participants will complete an online survey sent via a link to their mobile phone and will be mailed an OraQuick In-Home HIV Test kit . We will also estimate the total and incremental costs of the LifeSkills Mobile intervention relative to SOC, from healthcare sector and societal perspectives. Real World Applicability. Given inherent limitations to widespread dissemination of face-to...