Background: Advanced HIV disease is a major contributor to the slowing decline in HIV-related deaths globally. However, limited data exist on which individuals with advanced HIV are at highest risk of death. Methods: A retrospective cohort study was nested within a larger cohort of 13 primary care HIV treatment facilities in Khayelitsha, South Africa. All adults who had a CD4 count <200 cells/mm 3 between January 1, 2017, and March 31, 2021, were enrolled. Descriptive statistics were calculated, and the cohort was then restricted to those who had linked vital status information. We evaluated risk factors for mortality using Kaplan–Meier curves, and univariable and multivariable Cox proportional hazards models. Results: Between 19% and 28% of the larger cohort (n = 72,102) were estimated to have advanced HIV disease at any point during the study period. Of these individuals, 20% were on treatment, 40% were disengaged from care, and 40% were treatment naive at enumeration. Overall mortality was 12%, with mortality highest in the first year (6.8%) after enumeration. There were 608, 371, and 370 deaths among those disengaged, on antiretroviral therapy (ART), and ART naive, respectively, representing 14%, 17%, and 8% of individuals in each group. More than a quarter of all participants were found to have current tuberculosis at enrollment into the cohort. Conclusions: ART-exposed individuals with advanced HIV disease contribute substantially to ongoing HIV-related mortality in South Africa. Improved adherence and retention strategies within HIV programs could reduce this mortality.