Supplemental Digital Content is Available in the Text. Introduction: Safety-net health systems are key settings for HIV pre-exposure prophylaxis (PrEP) implementation, but little evidence is available about the frequency of PrEP prescribing in safety-net settings. We assessed PrEP prescribing among people with indications for PrEP at an urban safety-net health system that serves a county designated as an Ending the HIV Epidemic priority jurisdiction. Methods: We identified adults (aged 18 years or older) who engaged in primary care between January 2015 and December 2019 and had a documented indication for PrEP. PrEP indications included the presence of a behavioral or sexual risk factor of HIV acquisition or a positive bacterial sexually transmitted infection at the index visit. PrEP prescribing was defined as the proportion of patients with indications for PrEP who received a new prescription for PrEP. We estimated the cumulative incidence of PrEP prescription with corresponding 95% confidence limits (CL). Results: Our study population comprised 2957 individuals, of whom 58% was aged younger than 45 years, 56% was women, 67% was racial or ethnic minorities, and 60% was uninsured or provided care as part of a hospital-based managed care plan for individuals without insurance. We identified 41 individuals who were prescribed PrEP. The cumulative incidence of PrEP prescribing within 1 year of the first documented PrEP indication was 1.3% (95% CL: 0.91% to 1.7%). Conclusions: Our results suggest extremely low frequency of PrEP prescribing among people with indications for PrEP in an urban safety-net health system. Strategies are needed to improve PrEP implementation in high-priority populations and safety-net settings. [ABSTRACT FROM AUTHOR]