Both differentiation and function of CD4+ CD25 high naturally arising regulatory T cells (Treg), which play a key role in the control of autoimmunity, are thought to depend on TCR specificity. In the present study, we comparatively measured the αβTCR repertoire sizes of human peripheral blood Treg and CD4+ CD25− T cells by using a methodology based on PCR amplification and sequencing analysis. We show that Treg use a large unrestricted αβ TCR repertoire, the size and diversity of which are closely similar to those of CD4+ CD25− T cells, with a mean estimated size of 3.5× 10 6 distinct αβ TCR vs 4.7× 10 6 distinct αβTCR for CD4+ CD25− T cells. In addition, a 24% overlap between the repertoires of these two CD4+ subsets in the periphery is found. These data emphasize the intersection between naturally occurring Treg and effector T cell peripheral repertoires and provide new insights into the ontogeny of Treg in humans.