Overview. The goal of this project is to develop a multilevel HIV prevention approach to optimize and improve how we serve those at high risk for being missed by and/or falling off the HIV prevention cascade - people who use drugs (PWUD) who also belong to other key HIV risk groups (transgender women, men who have sex with men [MSM], Black/Latinx/Indigenous people). Specifically, the study will develop mSYNC, an mHealth SYNdemic-based, C&L psychology HIV prevention intervention for the emergency department (ED). Significance. Despite efficacious interventions for HIV, services are not reaching minoritized PWUD who continue to have high incidence. Syndemic theory proposes that co-occurring, mutually reinforcing psychosocial challenges (drug use, mental health, minority stress, unmet basic needs) drive HIV risk behavior and create barriers to care access. Alternative prevention efforts are needed to address this holistic syndemic HIV risk profile among minoritized PWUD and overcome historical barriers to reach. Due to low engagement in regular clinic-based care, minoritized PWUD have high utilization of drop-in care via EDs. With long wait times, ED visits are a prime opportunity to engage minoritized PWUD we are not reaching. Consultation-liaison (C&L) psychology offers a compelling framework to deliver a syndemic-targeted HIV intervention in the ED. Yet, EDs are overburdened with limited capacity to add services. mHealth could simulate human-delivered C&L with improvements such as continued on demand access to intervention content (individual-level intervention) and capacity build the ED to deliver integrated care for HIV prevention (hospital-level intervention). Guided by the Consolidated Framework for Implementation Research, development of mSYNC is grounded in implementation science to address pragmatic barriers to uptake within complexities of EDs and lives of minoritized PWUD. Objectives/Methods. To inform implementability and create a beta version of mSYNC, an mHealth user-centered design model approach will be used (Aim 1). Aim 2 will pilot test mSYNC to assess patient-level implementation outcomes of acceptability and appropriateness via a single-arm trial with N=100 minoritized PWUD in the ED. Secondarily, change over time will be explored for HIV risk, drug use, and mental health symptoms, and linkage to care. Assessments are at baseline, post-initial app use, and 30-, 60-, and 90- day via quantitative survey and exit interview. Aim 3 will evaluate hospital-level implementation outcomes of relative advantage and compatibility via a cross-sectional survey with ED stakeholders (N=30). Innovation/Impact. Aligned with NIH high priority areas, this study capitalizes on a unique merging of disciplines to produce an innovative, real-world, low threshold approach to address HIV disparities among those at highest risk for acquisition. The potential impact is development of a scalable tool that has trans-NIH applicability to other high priority h...