Epstein-Barr virus (EBV) is a widespread, persistent herpesvirus that can transform B cells and that is associated with malignant lymphomas. EBV dynamics and specific immunity in human immunodeficiency virus (HIV)-1-infected children are unknown. We found that, in 74% of EBV-seropositive, HIV-1-infected children, EBV DNA loads at the start of highly active antiretroviral therapy (HAART) were comparable with those in acutely EBV-infected, HIV-negative children. EBV DNA load remained elevated in most HIV-1-infected children for months to years of follow-up. Frequencies of interferon-γ-producing EBV-specific CD8 + T cells were comparable with those in healthy control children, and antibodies to EBV nuclear antigen were detected in 73% of EBV-seropositive children. Detectable EBV DNA load was not correlated with HIV-1 RNA level or with CD4+ T cell count increase after the start of HAART. Because of its resemblance to chronic active EBV, we studied the cellular tropism of EBV in these patients. EBV DNA was found not only in the CD19+ B cell fraction but also-at stable levels-in the CD4+ and CD8+ T cell fractions. Although the reason for the aberrant T cell tropism of EBV remains unclear, these data may provide an explanation for the differential EBV dynamics in the presence of normal serological findings. © 2006 by the Infectious Diseases Society of America. All rights reserved.