Natural varicella-zoster virus (VZV) infection and immunization with live attenuated varicella vaccine elicits T lymphocytes that recognize VZV glycoproteins, gpI-V, and the immediate early/tegument protein, the product of gene 62 (IE62). Proliferation or cytotoxicity assays, done under limiting dilution conditions to estimate responder cell frequencies, indicate no preferential recognition of VZV proteins by human T cells. Analysis of the primary cytotoxic T lymphocyte (CTL) response after vaccination demonstrates that both gpI and IE62 are targets of the early response. CD4+- and CD8+-mediated CTL recognition of these viral proteins can be detected with natural and vaccine-induced immunity. Responder cell frequencies for protein-specific T cell proliferation and CTL function are generally comparable in subjects with natural and vaccine-acquired immunity to VZV. Exogenous reexposure to VZV results in enhanced T cell proliferation and may be an important mechanism for maintaining virus-specific cellular immunity. Providing exogenous reexposure by giving varicella vaccine to individuals who have preexisting natural immunity markedly increases the responder cell frequencies of T cells that proliferate in response to VZV antigen and the numbers of circulating CTL that recognize VZV proteins.