In a small group of subjects we had identified persistent expansions (range 6–72%) of CD4 + CD8 + double-positive (DP) peripheral blood (PB) cells which express the CD8 α/α homodimer. Here, DP cells present in a larger cohort were further investigated and found by FACS analysis to express a single or a dominant TCRBV family. In these subjects, with a mean age of about 64 years, expansions of CD4 + cells with the same TCRBV family specificity as in the respective DP cells also were consistently detected. TCR heterogeneity of the dominant TCRBV family was specifically evaluated: The amplified CDR3 region was cloned and found to consist of one single or two largely dominant sequence patterns. Furthermore, cloning of the CDR3 region from FACS-sorted DP, CD4 + , or CD8 + cells indicates that both DP and CD4 + , but not CD8 + cells, isolated from the same individual possess a striking identity of the CDR3 regions. As indicated by FACS analysis, the clonally expanded cells occur in the CD4 + CD28 − cells. Taken together, these results suggest that expanded CD4 + CD28 − cells might also acquire CD8 α/α expression and become DP and imply that CD4 clonality is a more frequent phenomenon than previously suspected. In conclusion, the persistent expansions described in this report represent a novel group of age-related benign clonal expansions of still undefined significance of a rare CD28 − T cell subset.