PrEP persistence, or PrEP use over time, has been shown to be short, with most PrEP users stopping within 6–12 months. Furthermore, those most vulnerable to HIV often use PrEP for shorter periods. This qualitative study explores patient, provider, and contextual factors that influence PrEP persistence. In interviews with 25 PrEP users and 18 PrEP providers in San Francisco's safety net clinics, we analyze the perceived benefits and difficulties of taking PrEP, including structural barriers. We identify different steps in receipt of PrEP care (clinic visits and lab tests, pharmacy interactions, and medication adherence), and describe barriers and facilitators for providers and patients at each step. Our findings suggest that drop-in visits, streamlined testing, standing orders for labs, and 90-day PrEP prescriptions are highly desirable for many PrEP users. Also important are the proactive provision of adherence support and counseling, and referrals for housing, substance use, and mental health services.