The present study describes the persistent expansion of a subpopulation of circulating double-positive CD4⁺CD8⁺ T cells in a human immunodeficiency virus (HIV)—infected person over 8 years. The percentage of double-positive cells was remarkably stable with time and was not related to HIV plasma virus load. CD4⁺CD8⁺ cells exhibited phenotypic characteristics of activated memory T lymphocytes. Analysis of Vβ usage by the T cell receptors of these cells indicated restricted expression to the Vβ14 and Vβ17 families. Most CD4⁺CD8⁺ cells constitutively expressed cytotoxicity-associated molecules (C1.7 and perforin) and were selectively committed to produce interferon-γ and tumor necrosis factor-α, cytokines involved in cytotoxic function. The kinetics of changes in the relative proportion of single-positive CD4⁺ and double-positive CD4⁺CD8⁺ T cell subsets and a similar bias in Vβ usage by these subsets suggest that CD4⁺CD8⁺ lymphocytes originate from peripheral expansion of mature CD4⁺ T cells.