Peripheral CD4(+) CD8(+) T cells have been described in animals as well as in humans. Two distinct populations can be distinguished, namely CD4(lo) CD8(hi) and CD4(hi) CD8(lo) T cells. We demonstrate here that the increase in the number of peripheral CD4(+) CD8(+) T cells in the elderly is the result of an increase of the CD4(lo) CD8(hi) T-cell population. While the phenotype of CD4(lo) CD8(hi) and CD4(hi) CD8(lo) T cells was very similar in young persons, CD4(hi) CD8(lo), T cells from elderly subjects expressed a more differentiated phenotype and produced less interleukin-2 compared to CD4(lo) CD8(hi) T cells. In conclusion, our results suggest that aging leads to a phenotypic and functional difference between CD4(+) CD8(+) T-cell subsets. It may therefore be of relevance to distinguish between these subsets before assessing their functional significance in elderly humans.