The HIV epidemic varies significantly across and within different geographies in South Africa. Even though the epidemic is generalised, it is over-represented in some populations, including sex workers (SW) and men who have sex with men (MSM). It is also concentrated in the populations with very high vulnerability to HIV, such as adolescent girls and young women (AGYW). This contextual understanding of the HIV epidemic is critical to develop and implement effective HIV interventions. Differential vulnerability levels, social risk factors, high-risk sexual practices, and limited access to appropriate HIV interventions influence HIV incidence among these populations. These guidelines focus on the provision of PrEP as part of comprehensive combination prevention, drawing on implementation and research evidence and WHO recommendations.