The opioid and polysubstance epidemics could drive a surge in new HIV infections among people who inject drugs (PWID). Longstanding strategies to reduce HIV incidence, including syringe service programs, condom distribution, medications for opioid use disorder, and low-barrier HIV testing and treatment have not been adequate to eliminate transmission in this population. Although HIV pre-exposure prophylaxis (PrEP) is an evidence-based intervention that reduces HIV incidence among PWID, uptake in PWID has lagged due to limited PrEP knowledge, discrepancies between perceived and actual HIV risk, stigma, and structural barriers to adherence including homelessness and incarceration. In our efforts to deploy PrEP to PWID in our low-barrier substance use disorder bridge clinic, we have encountered another barrier: the HIV testing window period. We discuss challenges in delivering HIV exposure prophylaxis to the highest risk PWID, our current approach, and the need for more data to guide best practices.