Project Summary/Abstract Transgender women (TGW) are the population with the highest prevalence of HIV infection in the United States (US), with increasing numbers of new diagnoses from 2015-2019. Three types of pre-exposure prophylaxis (PrEP) have been shown to be highly effective in TGW, but uptake remains low in this population. TGW face a number of barriers in taking up and staying on PrEP, including pill fatigue from taking PrEP and hormone pills, concerns about reduced efficacy of gender-affirming hormones when taking PrEP, and concerns that PrEP works only for men who have sex with men (MSM), among other barriers. Many of these barriers could be alleviated by additional information or by choice of a different regimen. Decision support tools can be a useful adjunct to patient-led decision-making; a PrEP decision aid for cis-gender women in South Africa doubled PrEP uptake. We are adapting this tool (MyPrEP) for use in US English- and Spanish-speaking TGW. However, TGW likely need additional help in starting PrEP; therefore, we are combining MyPrEP with our bidirectional SMS communication tool (PrEPmate), the first CDC-endorsed evidence-based PrEP support tool shown to double PrEP adherence in young MSM. PrEPmate has already been adapted for TGW, but the PrEP navigation component of the tool has not fully incorporated addressing some of the social determinants of health that are barriers for TGW using PrEP. Therefore, in Aim 1, we will explore features of different PrEP modalities that are of greatest value to TGW and examine social determinants that may pose barriers to engaging in PrEP, through the use of formative research. We will conduct 6 focus groups in TGW (3 in English, 3 in Spanish, 5-7 TGW each) and conduct interviews with 8-10 PrEP providers for TGW, to explore these themes. Then, in Aim 2, we will adapt the MyPrEP patient-facing decision support tool for English- and Spanish-speaking TGW using iterative focus groups (2 in English, 2 in Spanish, 5-7 TGW each). These focus groups will meet 3 times over 3 months to provide input into the MyPrEP website for TGW, and to ensure it is culturally and linguistically appropriate for both English- and Spanish-speakers. Finally, in Aim 3, we will conduct a pilot randomized controlled trial with 40 TGW randomized to receive the combination of MyPrEP with PrEPmate (MyPrEP Plus), and 20 randomized to receive the control condition (pleaseprepme.org website). The RCT will evaluate the feasibility of MyPrEP Plus use (measured by use of both component tools) and compare the acceptability and PrEP uptake of MyPrEP Plus versus pleaseprepme.org. At the end of the MyPrEP Plus studies, we will have adapted MyPrEP Plus for English- and Spanish-speaking TGW, and will determine whether it holds enough promise to move forward into a fully powered, multi-site RCT in TGW to assess its impact on PrEP uptake, adherence, and persistence.