Introduction: we examined HIV-related social norms and perceptions among South African adolescents aged 15-18 years and evaluated their openness to using pre-exposure prophylaxis (PrEP) to reduce HIV risk. Methods: we analyzed cross-sectional data of 4,567 adolescents aged 15-18 years from the “fifth South African National HIV prevalence, HIV incidence, behaviour and communication survey (2017/2018)”. Outcomes of interest in our study were HIV-related social norms and awareness of HIV prevention methods, including pre-exposure prophylaxis (PrEP). Results: our results showed that compared to their female counterparts, a significantly higher percentage of male adolescents endorsed the statement “Men can have two or more sexual partners at the same time” (14.2% vs 10.1%, p=0.021). Condoms were the most popular method of HIV prevention, with 83.5% of all participants reporting awareness. Yet, 35.4% of those sexually active in the past year reported not using condoms all the time. Perceived parental sex education and exposure to community campaigns for HIV prevention were both associated with increased awareness of HIV prevention measures and openness to PrEP. Unaided recall of PrEP was very low (3.7%), but most of those who were HIV seronegative (69.3%) were open to using it after learning about it. Openness towards PrEP was significantly higher among those reporting vs not reporting past-year sexual activity (adjusted prevalence ratio (APR=1.16, 95%CI, 1.06-1.28), and binge-drinking (APR=1.24, 95%CI, 1.08-1.41). Conclusion: this study showed that while many South African adolescents were interested in trying PrEP, initial awareness was low. Ensuring barrier-free access to evidence-based preventive strategies may benefit public health.