The HIV epidemic in South Africa disproportionatery affects women, with young women aged 15–24 years three times more likely to be infected compared to young men. Gender inequalities increase women's vulnerability to HIV infection, white the HIV epidemic further entrenches gender inequalities. In this Focus, we use a ‘social exclusion’ framework to examine HIV and gender inequalities in South Africa. We argue that a relational understanding of social exclusion that focuses on processes driving health inequalities, rather than a static approach focusing on groups of ‘excluded’ people, offers the greatest analytical advantage. A lens foregrounding exclusionary processes can provide a new understanding of HIV and gender inequalities and thereby suggest new directions for policies and actions. Such a lens reveals the multidimensional and inter-related processes embedded in unequal power relationships that create social, political, cultural and economic inequalities whilst also highlighting the agency of oppressed individuals and groups. We conclude by arguing that policy action to address the profound inter-relationship between the epidemic of HIV and deeply embedded gender inequalities must begin with the primacy of universal human rights and women's rightful and equal inclusion to social systems; universal access to decent living standards, knowledge and access to quality education and health services.