BACKGROUND: HIV pre-exposure prophylaxis (PrEP) remains particularly underused among homeless-experienced people who use drugs (PWUD). SETTING: Boston Health Care for the Homeless Program, a Federally Qualified Health Center serving homeless-experienced individuals in Boston, Massachusetts. METHODS: To identify determinants of PrEP prescription initiation and continuation, we analyzed electronic medical records and pharmacy data between April 2018 and March 2022. Participants were HIV-negative and reported sexual, drug, or community-related HIV exposures. Adjusted multinomial logistic regression explored associations between sociodemographics, social vulnerabilities, behavioral factors (eg, injection drug use), and mental health and substance use disorder diagnoses with filling of 1 and more than 1 PrEP prescription. RESULTS: Among 509 participants, mean age was 38 years, 28% were women, 19% were Black, and 24% were Hispanic/Latino. At program enrollment, most were experiencing homelessness (92%), injecting drugs (78%), and living with a mental health disorder (71%). In multivariable-adjusted models, injection drug use was positively associated with filling 1 and more than 1 PrEP prescription (adjusted odds ratio [AOR]: 2.88, 95% confidence interval [CI]: 1.33 to 6.26; and AOR: 3.60, 95% CI: 2.02 to 6.42, respectively). Participants with opioid use disorder and generalized anxiety disorder were more likely to fill 1 and more than 1 prescription, whereas those with bipolar disorder were less likely to fill 1 prescription. No sociodemographic characteristics, sexual behaviors, or other mental health or substance use disorders were associated with study outcomes. CONCLUSIONS: A low-threshold, harm reduction-oriented PrEP program supported prescription initiation and continuation for homeless-experienced PWUD. Implementation research is needed to facilitate scale-up of this approach.