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Outcomes of HIV-infected children before widespread use of antiretroviral therapy (ART) for treatment and prevention of mother-to-child transmission (PMTCT) have been well characterized but less is known about children who acquire HIV infection in the context of good ART access.We enrolled newly diagnosed HIV-infected children ≤24 months of age at 3 hospitals and 2 clinics in Johannesburg, South Africa. We report ART initiation and mortality rates during 6 months from enrollment and factors associated with mortality.Of 272 children enrolled, median age 6.1 months, 69.5% were diagnosed during hospitalization. By 6 months postenrollment, 53 (19.5%) died and 73 (26.8%) were lost-to-follow-up. Using Kaplan–Meier analysis, the probability of death by 6 months after enrollment was 23.5%. The median age of death was 9.1 months [95% confidence interval (CI): 8.6–12.0]. Overall, 226 (83%) children initiated ART which was associated with a 71% reduction in risk of death [hazard ratio (HR) = 0.29 (95% CI: 0.15–0.58)]. In multivariable analysis of infant factors, weight-for-age Z score < −2 standard deviation (SD) [HR = 2.43 (95% CI: 1.03–5.73)], CD4 <20% [HR = 3.29 (95% CI: 1.60–6.76)] and identification during hospitalization [HR = 2.89 (95% CI: 1.16–7.25)] were independently associated with mortality. In multivariable analysis of maternal factors, CD4 ≤350/no maternal ART was associated with increased mortality risk [HR = 2.57 (95% CI: 1.19–5.59)] versus CD4 >350/no maternal ART; exposure to maternal/infant antiretrovirals for PMTCT was associated with reduced mortality risk [HR = 0.53 (95% CI: 0.28–0.99)] versus no PMTCT.ART initiation is highly protective against death in young children. However, despite improved access to ART, young children remain at risk for early death; innovative approaches to rapidly diagnose and initiate treatment as early in life as possible are needed.