Herpes zoster (HZ) is a frequent complication of advanced human immunodeficiency virus (HIV) infection. We determined the effect of highly active antiretroviral therapy (HAART) on reconstitution of varicella-zoster virus (VZV)-specific cell-mediated immunity (VZV-CMI) in 56 VZV- and HIV-infected children. VZV-CMI did not change over the course of >/=3 years of observation, despite a reduction in HIV load. VZV-CMI correlated with lower HIV load but not with CD4 cell percentage. The incidence of HZ was unaffected by HAART. None of 5 patients who developed HZ during the study had VZV-CMI before developing HZ. After developing HZ, only the 2 HAART-compliant patients developed VZV-CMI. Thus, VZV-specific immune reconstitution in HIV infection may require antigenic reexposure, in addition to control of HIV replication.