BackgroundHIV disproportionately affects Black/African American cisgender women (hereafter women) in the United States. Despite its proven effectiveness, pre-exposure prophylaxis (PrEP) for HIV prevention remains vastly under-prescribed to women based on their need. Increasing PrEP uptake and persistence among women is crucial to reducing HIV transmission; however, there have been few studies designed specifically for women. This article describes the study protocol used to assess the feasibility, acceptability, and effectiveness of implementation strategies to improve PrEP uptake and persistence among Black women in the Midwest and South.MethodsPrEPOptimization amongWomen toEnhanceRetention andUptake (POWER Up) is an evidence-based, woman-focused set of five implementation science strategies that addresses barriers of PrEP utilization at the provider, patient, and clinic levels. POWER Up includes 1) routine PrEP education for patients, 2) standardized provider training, 3) electronic medical record (EMR) optimization, 4) PrEP navigation, and 5) PrEP clinical champions. These strategies will be adapted to specific clinics for implementation, tested via a stepped-wedge trial, and, if effective, packaged for further dissemination.DiscussionWe will utilize a stepped-wedge cluster randomized trial (SW-CRT) to measure change in PrEP utilization across diverse geographic areas. Preparation for adapting and implementing the bundle of strategies is needed to determine how to tailor them to specific clinics. Implementation challenges will include adapting strategies with the available resources at each site, maintaining stakeholder involvement and staff buy-in, adjusting the study protocol and planned procedures as needed, and ensuring minimal crossover. Additionally, strengths and limitations of each strategy must be examined before, during, and after the adaptation and implementation processes. Finally, the implementation outcomes of the strategies must be evaluated to determine the real-world success of the strategies. This study is an important step toward addressing the inequity in PrEP service delivery and increasing PrEP utilization among Black women in the U.S.