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Research Objective: Emerging studies suggest that people with disabilities are at a higher risk for HIV. However, less is known about impact of maternal disability and HIV on child mortality. We aimed to examine the potential compounding effect of maternal disability and HIV status on child mortality in South Africa. Study Design: We analyzed data for women age 15–49 years from South Africa, using the nationally representative 2016 South Africa Demographic and Health Survey. We estimated unadjusted and adjusted risk ratios of child mortality indicators by maternal disability and maternal HIV using modified Poisson regressions. Population Studied: Mothers without disabilities who were HIV–negative were used as referent, and we analyzed cohorts of (1) mothers with disabilities who are HIV–negative, (2) mothers without disabilities who are HIV–positive, and (3) mothers with disabilities who are HIV–positive. Principal Findings: Children born to disabled mothers compared to their peers born to non–disabled mothers were at a higher risk for neonatal mortality (RR = 1·80, 95%CI:1·31–2·49), infant mortality (RR = 1·69, 95%CI:1·19–2·41), and under–five mortality (RR = 1·78, 95%CI:1·05–3·01). The joint risk of maternal disability and HIV–positive status on the selected child mortality indicators is compounded such that it is more than the sum of the risks from maternal disability or maternal HIV–positive status alone (RR = 3·97 vs. joint RR = 3·67 for neonatal mortality, RR = 3·57 vs. joint RR = 3·25 for infant mortality, and RR = 6·44 vs. joint RR = 3·75 for under–five mortality). Conclusions: The findings suggest that children born to HIV–positive women with disabilities are at an exceptionally high risk of premature mortality. Given that maternal HIV and disability amplify each other's impact on child mortality, addressing disabled women's HIV–related needs and understanding the pathways and mechanisms contributing to these disparities is crucial. Implications for Policy or Practice: These findings emphasize that it is critical for policymakers, donor agencies, and non–governmental organizations to consider the intersection of disability and HIV in developing policy and practice in the context of achieving targets of reducing child mortality under the Sustainable Development Goals (SDGs) in the Global South. Primary Funding Source: Cardno Emerging Markets, USA, Ltd. [ABSTRACT FROM AUTHOR]