The Centers for Disease Control and Prevention estimates that one in four sexually active men who have sex with men (MSM) could decrease their HIV risk by using HIV pre-exposure prophylaxis (PrEP). Because many MSM access healthcare from primary care providers (PCPs), these clinicians could play an important role in providing access to PrEP. Semistructured qualitative interviews were conducted with 31 PCPs in Boston, MA, to explore how they approach decisions about prescribing PrEP to MSM and their experiences with PrEP provision. Purposive sampling included 12 PCPs from an urban community health center specializing in the care of lesbian, gay, bisexual, and transgender persons (“LGBT specialists”) and 19 PCPs from a general academic medical center (“generalists”). Analyses utilized an inductive approach to identify emergent themes. Both groups of PCPs approached prescribing decisions about PrEP as a process of informed decision-making with patients. Providers would defer to patients' preferences if they were unsure about the appropriateness of PrEP. LGBT specialists and generalists were at vastly different stages of adopting PrEP into practice. For LGBT specialists, PrEP was a disruptive innovation that rapidly became normative in practice. Generalists had limited experience with PrEP; however, they desired succinct decision-support tools to help them achieve proficiency, because they considered preventive medicine to be central to their professional role. As generalists vastly outnumber LGBT specialists in the United States, interventions to support PrEP provision by generalists could accelerate the scale-up of PrEP for MSM nationally, which could in turn decrease HIV incidence for this priority population.