Copyright © 2014 by Lippincott Williams & Wilkins. Background: Increased exposure to a broad array of pathogens in children residing in sub-Saharan Africa may lead to heightened immune activation and increased proportions of memory T cells. Changes in the size of these cellular subsets have implications for restoration of normal immune function after treatment with highly active antiretroviral therapy (HAART) and are not well characterized in young sub-Saharan African children. Methods: CD4+ and CD8+ T-cell subsets were measured by flow cytometry in 157 HIV-infected Zambian children before and at 3-month intervals during HAART for up to 30 months and in 34 control children at a single study visit. Results: Before HAART, HIV-infected children had higher levels of activated and effector memory (EM) CD4+ and CD8+ T cells, and lower levels of naive T cells and CD8+ T cells expressing IL-7Rα, compared with control children. The median duration of follow-up was 14.9 months (interquartile range, 6.4-23.2) among 120 HIV-infected children with at least 1 study follow-up visit. Levels of immune activation and EM CD4+ T cells declined within 6 months of HAART, but the percentages of EM CD4+ T cells and effector CD8+ T cells remained elevated through 30 months of HAART. IL-7Rα-expressing CD8+ T cells increased with HAART, suggesting expansion of memory capacity. Conclusions: HAART significantly reduced levels of immune activation and EM CD4+ T cells, and promoted reconstitution of naive T cells and IL-7Rα-expressing CD8+ T cells. However, persistently high levels of EM CD4+ T cells in HIV-infected children may reflect chronic perturbations in T-cell subset composition.