INTRODUCTION: Adolescent girls and young women (AGYW) remain disproportionately affected by HIV. In a rural area of South Africa with an annual incidence (2011-2015) of 5 and 7% per annum for 15-19 and 20-24-year olds respectively, oral pre-exposure prophylaxis (PrEP) could provide AGYW with a form of HIV prevention they can more easily control. Using quantitative and qualitative methods, we describe findings from a study conducted in 2017 that assessed knowledge of and attitudes toward PrEP to better understand community readiness for an AGYW PrEP rollout. METHODS: We used descriptive analysis of a quantitative demographic survey (n = 8,414 ages 15-86) to identify population awareness and early PrEP adopters. We also conducted semi-structured, in-depth interviews with a purposive sample of 52 potential PrEP gatekeepers (health care workers, community leaders) to assess their potential influence in an AGYW PrEP rollout and describe the current sexual health landscape. Interviews were recorded, transcribed, and iteratively coded to identify major themes. RESULTS: PrEP knowledge in the general population, measured through a demographic survey, was low (n = 125/8,414, 1.49% had heard of the drug). Medicalized delivery pathways created hostility to AGYW PrEP use. Key informants had higher levels of knowledge about PrEP and saw it as a needed intervention. Community norms around adolescent sexuality, which painted sexually active youth as irresponsible and disengaged from their own health, made many ambivalent towards a PrEP rollout to AGYW. Health care workers discussed ways to shame AGYW if they tried to access PrEP as they feared the drug would encourage promiscuity and "risky" behaviour. Others interviewed opposed provision on the basis of health care equity and feared PrEP would divert both drug and human resources from treatment programs. CONCLUSIONS: The health system in this poor, high-HIV incidence area had multiple barriers to a PrEP rollout to AGYW. Norms around adolescent sexuality and gatekeeper concerns that PrEP could divert health resources from treatment to prevention could create barriers to PrEP roll-out in this setting. Alternate modes of delivery, particularly those which are youth-led and demedicalize PrEP, must be explored.