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There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2–5 y of age. This study uses a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS–Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2–5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm3 or CD4 percentage (CD4%) <25%