Background <p>Women involved in the criminal legal system have elevated rates of opioid use disorder, which is treatable, and HIV, which is preventable with pre-exposure prophylaxis (PrEP). There are significant social and structural barriers to integrated delivery of PrEP and medications for opioid use disorder (MOUD), limiting women’s ability to access these life-saving interventions. In a two parallel-arm randomized controlled trial, we are assessing an innovative eHealth delivery model that integrates PrEP with MOUD and is tailored to meet the specific needs of women involved in the criminal legal system.</p> Methods <p>We will recruit and enroll 250 women involved in the criminal legal system with opioid use disorder across two diverse settings (New Haven, CT and Birmingham, AL). Participants will be randomized to (a) the “Athena strategy,” which includes a PrEP decision aid and integrated PrEP/MOUD delivery via eHealth; or (b) enhanced standard of care (SOC) that includes a decision aid-only. During 6-month follow-up, we will assess PrEP initiation as the primary clinical outcome and implementation outcomes that include acceptability, adoption, feasibility, fidelity, implementation cost, and sustainability.</p> Discussion <p>Results could help determine if reducing the social and structural barriers to PrEP and MOUD for women involved in the criminal legal system will facilitate engagement in treatment and prevention services, thus alleviating health disparities.</p> Trial registration <p>Clinicaltrials.gov (NCT05547048). Registered September 15, 2022. <a href="https://clinicaltrials.gov/study/NCT05547048?term=NCT05547048&amp;rank=1">https://clinicaltrials.gov/study/NCT05547048?term=NCT05547048&amp;rank=1</a>.</p>