Prior to issuing formal HIV pre-exposure prophylaxis (PrEP) clinical practice guidelines in 2014, the US Centers for Disease Control and Prevention (CDC) had released interim guidance for oral PrEP use among adults. Because oral PrEP may be used off-label for youth and may soon be indicated for minor adolescents, we examined the potential adoption of the interim guidance among clinicians who care for HIV-infected and at-risk youth. Individual, semi-structured interviews were conducted with 15 US clinicians who were recruited through an adolescent HIV research network. The theory-driven interview guide, consisting primarily of open-ended questions, assessed demographics, familiarity with the guidance, attitudes toward the guidance, and attitudes toward the use of the guidance for adult and adolescent patients. Transcripts were analyzed using framework analysis. Most clinicians (11/15) reported that the guidance was compatible with their practice, although several reported that some aspects, particularly frequency of follow-up visits, needed to be tailored to meet their patients' needs. We found variability in clinician reported characteristics of appropriate PrEP candidates (e.g., youth with substance use and mental health issues were noted to be both suitable and unsuitable PrEP candidates) and PrEP use in serodiscordant couples (e.g., whether PrEP would be recommended to a patient whose HIV-infected partner is virally suppressed). Clinician reported steps for initiation, monitoring, and discontinuing PrEP were largely consistent with the guidance. The observed variability in clinician practice with regard to oral PrEP may be reduced through interventions to educate clinicians about the content and rationale for guideline recommendations.