HIV pre-exposure prophylaxis (PrEP) remains underutilized in the US due to an array of structural, provider, and individual-level barriers. These include low PrEP awareness in people at increased HIV risk, their limited engagement with healthcare systems, and a paucity of providers with the knowledge and willingness to initiate PrEP. Emergency Departments (EDs) are strategic locations for identifying PrEP-eligible individuals: they serve people at disproportionate risk for HIV infection due to intersecting social-structural vulnerabilities; and they have demonstrated their capacity for initiating PrEP based on successful implementation of routine offers of HIV testing and provision of post-exposure prophylaxis. However, there are no evidence-based models for EDs to adopt that successfully screen, educate and motivate, initiate, and link ED patients to PrEP. A successful strategy needs to address several challenges, including an ED culture that prioritizes urgent and emergent tasks over preventive interventions and patients’ PrEP hesitancy, particularly in the context of an ED visit for a non-PrEP- related issue. In this R34, a partnership of experienced clinician researchers from Mount Sinai Beth Israel Department of Emergency Medicine, researchers from the HIV Center for Clinical and Behavioral Studies at NYS Psychiatric Institute and Columbia University, researchers from the Einstein-Rockefeller-CUNY CFAR at the Albert Einstein College of Medicine, and an Expert Panel of ED providers, community-based organization leaders, and policymakers, we will elaborate, iteratively refine, and pilot in a randomized trial (RCT) a comprehensive PrEP intervention package—PrEP-ED—designed to address these challenges. The specific aims are to: Aim 1a. Identify patient preferences for receiving PrEP services in the ED through a discrete-choice experiment (DCE) among ED patients. Aim 1b. Along with the Expert Panel, revise and elaborate strategies for each step in the ED-PrEP cascade—screening, education, acceptance, and linkage to ongoing care, using the DCE findings and drawing on experiences of the Expert Panel. Aim 2. Implement the package developed in Aim 1 in an ED setting and iteratively optimize each component. Aim 3a. Conduct a Hybrid Implementation-Effectiveness Type 2 pilot randomized controlled trial, comparing PrEP-ED as optimized in Aim 2 to referral to PrEP services only. Aim 3b. Guided by the Consolidated Framework for Intervention Research, explore qualitatively domains relevant to future implementation. This proposal addresses the “prevent” pillar of the HIV National Strategic Plan and the Office of AIDS Research priority to reduce HIV incidence. By identifying feasible and effective approaches to PrEP assessment, education/motivation, acceptance, and linkage in the ED our intervention could make a major contribution to population-level prevention and reduction of HIV disparities.