Modified Project Summary/Abstract Section Despite the availability of biomedical prevention tools to end the HIV epidemic, incidence of HIV and other STIs in Alabama remain high, while uptake of prevention such as PrEP remains low. Sex workers and people who use drugs represent vulnerable groups who face unique barriers to HIV prevention including PrEP. However, HIV services for sex workers in Alabama are limited, and no evidence-based interventions in the CDC’s Compendium have been tailored for sex workers. To assess syndemics trends among sex workers in Birmingham, in Year 1 of this study we analyzed 16 years of data from nearly 25,000 visits and over 17,000 individuals accessing services at Birmingham AIDS Outreach (community partner) and 1,185 individuals reporting sex work, finding elevated HIV and syphilis prevalence among sex workers of color and elevated HCV prevalence among non-Hispanic white sex workers. In our qualitative interviews with 12 people engaged in sex work and five key informants from BAO and other organizations, we contextualized sex workers’ experiences, finding that sex work in Birmingham varies in terms of social and structural vulnerabilities and HIV/STI risk. However, most programs offer tailored services to specific populations, and gaps in care remain. Thus, using syndemic theory, we will develop an intervention for people engaging in sex work in Alabama in the proposed Year 2 of this study that builds on mixed methods data obtained in Year 1. The Specific Aims are to: (1) Identify and characterize geographic clustering of sex work and related outcomes among BAO clients, (2) Develop a harm reduction intervention for people engaging in sex work, and (3) Assess preliminary acceptability, appropriateness, and feasibility of the intervention to increase PrEP uptake that responds to the syndemics of sex work, drug use, HIV, and STIs. In Aim 1, we will apply spatial epidemiologic methods to identify geographic clustering of sex work among BAO clients; characterize cluster-level differences in clinical and behavioral outcomes; and assess the relationship between neighborhood-level factors (e.g., structural racism) and cluster- and individual-level clinical and behavioral outcomes. In Aim 2, the study team and partners will develop the intervention using the principles of co-design, while in Year 3 we will evaluate the acceptability, appropriateness, and feasibility of the intervention using validated measures through web-based surveys and qualitative interviews with sex workers (n=5) and stakeholder interviews with providers and other key informants (n=5). This work will be guided by the Consolidated Framework for Implementation Research (CFIR), RE-AIM framework, and ERIC strategies. The project will inform a subsequent R-level proposal to implement and evaluate the effectiveness of this novel intervention co- developed with community members.