PROJECT ABSTRACT Adolescent girls and young women (AGYW) aged 15-24 are twice as likely to be living with HIV than young men in Sub-Saharan Africa (SSA). HIV prevention strategies available to AGYW primarily depend on male partner cooperation, limiting the ability for these strategies to reduce HIV spread. Oral pre-exposure prophylaxis (PrEP) is a highly effective biomedical HIV prevention method. Unlike other prevention strategies, PrEP holds tremendous promise as a female-controlled prevention approach, giving AGYW more self-efficacy and agency to minimize HIV risks. However, as effective as PrEP has been, it is underutilized. Lack of social support, disclosure concerns, stigma and discrimination, financial costs associated with transport to clinics and food to accompany medication are still major barriers. Peer support interventions and PrEP awareness via peers has been associated with increased PrEP uptake. However, these approaches may not be as effective when delivered alone –given that poverty-associated factors, too, greatly undermine PrEP access, uptake and adherence. Thus, combining multilevel interventions, in this case, combining peer support with economic empowerment (EE) targeting poverty and financial constraints, may offer additive effects to overcome these barriers. Combination multi-level interventions focused on poverty reduction, behavioral health, and HIV treatment outcomes among youth affected by HIV, including AGYW in SSA have demonstrated effectiveness in regard to health services uptake and addressing social determinants of health. Our team is currently implementing a randomized clinical trial (R01MH116768) that includes HIV risk reduction (HIVRR) sessions and PrEP uptake among 542 women (ages 18+) engaged in commercial sex work in Uganda. We assessed women’s acceptability of PrEP. Among HIV negative women who had not initiated PrEP (n=286), 45% declined PrEP, due to inability to adhere to daily medication and fear of stigma. Overcoming these barriers is critical to ending the HIV epidemic among AGYW. We propose a multilevel combination intervention focused on PrEP initiation and adherence among AGYW living in HIV hotpots in Uganda. Suubi(hope)4PrEP will combine: 1) HIVRR that incorporates sessions on PrEP, 2) peer supporters (PS) with lived experiences taking PrEP to facilitate linkage to and continued care, and 3) EE components targeting financial barriers associated with PrEP access. We will randomly assign 600 AGYW (at the community level) to one of the three study arms (n=200 AGYW, n=10 sites per arm): 1) HIVRR only, 2) HIVRR+ PS, or 3) HIVRR + PS + EE. Specific aims are: Aim 1. Examine the impact of Suubi4PrEP on PrEP initiation and adherence. Aim 2. Examine the effect of Suubi4PrEP on hypothesized mechanisms of change and intervention mediation. Aim 3. Use mixed methods to explore multi- level factors that influence PrEP initiation and adherence using CFIR. Aim 4. Assess the cost and cost- effectiveness of the interventions. Suubi4PrEP aligns with NIH’s priorities to reduce HIV incidence and HIV- related health disparities by gender through PrEP as a prevention treatment.