Objective: Oral preexposure prophylaxis (PrEP) is highly effective in preventing HIV-1 acquisition, yet it is underutilized among at-risk populations. In this pilot quality improvement (QI) initiative, we sought to identify barriers to PrEP implementation and create interventions to improve access to PrEP in a primary care clinic for homeless veterans. Methods: The setting was a large homeless primary care clinic at the Veterans Affairs in an urban area with high HIV prevalence. A root cause analysis was performed to identify barriers to PrEP expansion in the primary care clinic. Targeted interventions to improve provider knowledge and patient access to PrEP were implemented by the QI team. Results: Root cause analysis revealed 3 primary barriers to PrEP expansion in the primary care clinic: institutional limitations for prescribing PrEP, inconsistent screening and recognition of eligible patients by clinic staff, and lack of clinic workflow processes to support PrEP prescription. A multidisciplinary focus group found low levels of PrEP awareness and knowledge, with only 22% of providers reporting comfort discussing PrEP with patients. This improved to 40% of providers following targeted clinic educational interventions. The QI team also developed a pathway for primary care providers to obtain institutional PrEP prescribing privileges and used work groups to develop clinic workflows and protocols for PrEP. At the end of the intervention, at least 50% of primary care providers in the clinic had initiated PrEP in a new patient. Conclusions: We describe a multidisciplinary QI model to implement PrEP within a primary care setting serving Veterans and persons experiencing homelessness. Our program successfully addressed provider knowledge deficits and improved primary care capacity to prescribe PrEP. The primary care clinic can be a viable and important clinical setting to improve access to PrEP for HIV prevention, especially for vulnerable populations.