The political economy of the AIDS crisis in South Africa’s past can be understood in terms of the concept of health justice. In particular, health justice can help us interpret the history of AIDS in South Africa according to the intersecting manifestations of socioeconomic inequality in the country, including the migrant labor system, the apartheid-era health system, with its racial segregation and inferior service provision for black people, the feminization of poverty, and, legal and institutionalized homophobia and transphobia. We can also use the overarching concept of health justice to understand the histories of public health and progressive health advocacy in relation to the epidemic over three periods. First, early in the history of the disease in South Africa, health injustice was manifest in the socioeconomic phenomena behind its arrival in the country in 1982. Secondly, its subsequent entrenchment in the country in the pre-1994 period can be related to South Africa’s late-apartheid political economy. Thirdly, in the postapartheid period, the Nelson Mandela (1994–1999) and Thabo Mbeki (1999–2008) administrations exhibited deficits in political will in the development of effective AIDS policies, most notably evident in Mbeki’s AIDS denialism. In response to this, in 1998 the Treatment Action Campaign (TAC) emerged from the AIDS advocacy of various strands of antiapartheid activism. The last section highlights how the TAC’s activism influenced global health politics from the late 1990s to the early 2000s. This history points to the TAC’s valuable legacy of activism in addressing AIDS and general health injustices. Interpreting the socioeconomic and political history of AIDS is of wider relevance to important historiographical bodies of literature in relation to South Africa, including those around medicine and health, gender and sexuality, black politics and social movements, and, South Africa’s role in world history. The topic is therefore especially deserving of sustained study.