BackgroundThe United States' (U.S.) initiative to End the HIV Epidemic aims to reduce new HIV infections in areas of high HIV prevalence. Despite national efforts to reduce HIV incidence, cisgender women continue to represent approximately one out of every five new HIV diagnoses in the U.S. Taking pre-exposure prophylaxis (PrEP) is an effective HIV prevention strategy; however, PrEP initiation among cisgender women is suboptimal, with only 10% of eligible women receiving PrEP prescriptions in 2019.MethodsWe designed a trial to test the effectiveness of interventions to increase PrEP initiation, while evaluating the implementation strategy (hybrid type II trial) in seven obstetrics and gynecology (OB/GYN) clinics (two federally qualified health centers, three community-based, and two academic) in Baltimore, Maryland. A total of 42 OB/GYN providers will be enrolled and randomized (1:1:1) into one of three clinical trial arms (standard of care, patient-level intervention, or multi-level intervention). Eligible patients of enrolled providers will receive a sexual health questionnaire before their appointment through the electronic health record’s (EHR) patient portal. The questionnaire will be scored in three tiers (low, moderate, and high) to assess HIV risk. Patients at low risk will be offered an HIV test only, while those who score medium or high risk will be included in the clinical trial and assigned to the clinical trial arm associated with their provider. Differences in PrEP initiation, our primary outcome, across the three arms will be analyzed using generalized linear mixed-effect models with logistic regression. We will adjust results for demographic differences observed between arms and examine PrEP initiation stratified by patient’s and provider’s race and ethnicity.Additionally, a comprehensive economic analysis for each intervention will be conducted.DiscussionWe hypothesize that gathering information on sensitive sexual behaviors electronically, communicating HIV risk in an understandable and relatable format to patients and OB/GYN providers, and deploying EHR alerts will increase PrEP initiation and HIV testing.Trial RegistrationThe trial is registered withClinicalTrials.gov(NCT05412433) on 09 June 2022.https://clinicaltrials.gov/ct2/show/NCT05412433?term=NCT05412433&draw=2&rank=1.