Patients with genital herpes have frequent viral reactivations. The repeated antigenic rechallenges can modulate the CD4+ memory T-cell repertoires during the course of infection. In this study, the CD4+ T-cell responses against the herpes simplex virus type 2 (HSV-2) tegument protein VP16 were studied in two HSV-2-infected subjects at two different time points that spanned a 5-year period. Although the VP16-specific T cells did exhibit variation of T-cell receptor Vbeta usages at the two time points, T cells that used identical Vbeta and CDR3 junction sequences were also observed at the two time points. These experiments demonstrate that the CD4+ T cells that are directed against HSV-2 VP16 protein in chronically infected individuals are oligoclonal and that T cells of specific clonotypes can be maintained throughout the course of the disease.