PROJECT SUMMARY/ABSTRACT The overall goal of this mixed-methods study is to examine the effectiveness of a same-day pre-exposure prophylaxis (PrEP) initiation program in Jackson, Mississippi, and to explore barriers and facilitators to PrEP initiation and retention in this model of PrEP delivery. HIV remains a critical public health problem in the United States (US), with minimal decreases in HIV incidence in the past five years. There are substantial disparities in HIV incidence and PrEP uptake in the US – by geography and race/ethnicity – that have persisted for decades. Mississippi is one of seven states identified by the federal Ending the HIV Epidemic (EHE) initiative as a “geographic hotspot” of HIV. MS has the sixth highest rate of new HIV diagnosis in the US, with the rate among Black Mississippians being eight times higher than White Mississippians. In 2018-2019 we initiated a pharmacist-led, same-day PrEP initiation program in Jackson to integrate same-day PrEP initiation at the time of HIV testing, with a goal of facilitating rapid increase of PrEP uptake in non-clinical settings in Jackson. Over 75% of individuals who were offered same-day PrEP filled the prescription and about half were linked into ongoing PrEP care. The program has continued operating with local funds, and new resources from the EHE could be leveraged to expand Rapid PrEP. However, gaps in the model's evidence base limit its scalability elsewhere. Here we propose a series of studies using prospective and retrospective data that will directly inform whether resources should be allocated to scaling-up Rapid PrEP or to developing alternative models of PrEP delivery. First, we will estimate the effectiveness of Rapid PrEP by examining PrEP persistence and HIV incidence among individuals who initiated PrEP via Rapid PrEP (N=121) compared to a group of individuals who initiated PrEP in a traditional “status quo” clinic-based model in Jackson, MS in 2015-2019 (N=475). We will use prescription fill data to compare the 12-month PrEP persistence between the two groups. In sub- analyses, we will restrict the population to those who were diagnosed with an STI after starting PrEP (a group at high ongoing risk of HIV) and compare PrEP persistence. We will also use MS State HIV surveillance data to compare HIV incidence between the two groups. Second, we will conduct 10-15 one-on-one qualitative interviews with Rapid PrEP participants who disengaged from PrEP care to investigate the barriers and facilitators to PrEP initiation and persistence. We will interview 3-4 Rapid PrEP participants who disengaged at each step of the Rapid PrEP continuum (e.g., filling the prescription, initial linkage to clinical care, and maintenance in PrEP care). Findings from these studies will direct the use of EHE resources to either scale-up Rapid PrEP or to develop new models of PrEP delivery that can be operationalized in settings of low clinical capacity.