The neurological impact of Human Immunodeficiency Virus (HIV) on children includes loss of brain growth, motor abnormalities and cognitive dysfunction. Despite early antiretroviral treatment (ART) intervention to suppress viral load, neurological consequences of perinatal HIV-1 infection persist. Utilizing the pediatric simian immunodeficiency virus (SIV) infection model, we tested the hypothesis that early-life SIV infection depletes neuronal population in the hippocampus. A total of 22 ART-naïve infant rhesus macaques (Macaca mulatta) from previous studies were retrospectively analyzed. Infant macaques were either intravenously (IV) inoculated with highly virulent SIVmac251 at ~1 week of age and monitored for 6–10 weeks, or orally challenged with SIVmac251 from week 9 of age onwards with a monitoring period of 10–23 weeks post-infection (19–34 weeks of age), and SIV-uninfected controls were euthanized at 16–17 weeks of age. We have previously reported that the IV SIVmac251-infected neonatal macaques (Group 1) displayed a 42% neuronal reduction throughout the hippocampal cornu ammonis (CA) fields. The orally-infected infant macaques displayed a 75% neuronal reduction in the CA1 region compared to controls and 54% fewer neurons than IV SIV infants. The CA2 region showed a similar pattern, with a 67% reduction between orally-infected SIV subjects and controls and a 40% difference between IV-and orally-infected SIV groups. In the CA3 region, there were no significant differences between these groups, however both SIV-infected groups had significantly fewer pyramidal neurons than control subjects. There was no correlation between plasma viral load and neuronal populations in any of the CA fields. The loss of hippocampal neurons may contribute to the rapid neurocognitive decline associated with pediatric HIV infection. While each subfield showed vulnerability to SIV infection, the CA1 and CA2 subregions demonstrated a potentially enhanced vulnerability to pediatric SIV infection. These data underscore the need for early diagnosis and treatment, including therapeutics targeting the central nervous system (CNS).