Human cytomegalovirus (HCMV) persists after infection but is controlled by cellular immune responses, particularly by CD8+ T cells. If infected individuals are immunosuppressed, HCMV can be reactivated. Upon testing the blood of healthy donors with human lymphocyte antigen tetramers, we found one individual with about 50% of his CD8+ T cells being specific for the immunodominant pp65 epitope NLVPMVATV Over a period of 2 years the high level of HCMV-specific T cells was maintained, and no HCMV DNA could be detected. At one timepoint, however, HCMV-specific DNA was detected, while 65% of CD8+ T cells were specific for HCMV. When virus was detectable, a lower percentage of HCMV-specific CD8+ T cells showed interferon gamma (IFN-gamma) production after peptide stimulation in vitro. These data suggest that HCMV reactivation may also occur in immunocompetent persons, accompanied by the presence of HCMV-specific CD8+ T cells which are not producing IFNy, and therefore potentially anergic or in vivo exhausted.