BACKGROUND : High antenatal HIV seroprevalence rates (∽30%) with low perinatal HIV transmission rates (2.5%) due to HIV prevention of mother-to-child transmission program improvements in South Africa, has resulted in increasing numbers of HIV-exposed-uninfected (HEU) children. We aimed to describe the epidemiology of invasive pneumococcal disease (IPD) in HEU infants. METHODS : We conducted a cross-sectional study of infants aged <1 year with IPD enrolled in a national, laboratory-based surveillance program for incidence estimations. Incidence was reported for two time points, 2009 and 2013. At enhanced sites we collected additional data including HIV status and in-hospital outcome. RESULTS : We identified 2099 IPD cases in infants from 2009-2013 from all sites. In infants from enhanced sites (n=1015), 92% had known HIV exposure status and 86% had known outcomes. IPD incidence was highest in HIV-infected infants, ranging from 272-654/100,000 population between time points (2013 and 2009), followed by HEU (33-88/100,000) and HIV-unexposed-uninfected (HUU) infants (18-28/100,000). Case fatality rate in HEU (29%, 74/253) was intermediate between HUU (25%, 94/377) and HIV-infected infants (34%, 81/242). When restricted to cases <6 months of age, HEU infants (37%, 59/175) were at significantly higher risk of dying than HUU infants (32%, 51/228; Adjusted relative risk ratio = 1.76 [95% confidence interval 1.09-2.85]). DISCUSSION : HEU infants are at increased risk of IPD and mortality from IPD compared with HUU children, especially as young infants. HEU infants, whose numbers will likely continue to increase, should be prioritized for interventions such as pneumococcal vaccination along with HIV-infected infants and children.