The selection of T lymphocytes in the thymus and their activation upon the encounter with foreign antigens in the periphery require the aggregation and signals of the T cell receptor (TcR)/CD3 complex and several surface molecules termed coreceptors (notably CD4 or CD8 and CD45). The spatial arrangement and interactions of the different molecules in the resulting multimolecular recognition structure are mostly unknown. Here we report, from studies on a healthy human CD3 gamma deficiency, that the lack of the CD3 gamma component of the TcR/CD3 complex is associated with a long-term severe defect of peripheral blood CD4+ CD45RA+ and CD8+ lymphocytes, whereas CD4+CD45RO+, B and natural killer lymphocytes are unaffected. These results suggest that the CD3 gamma site of the TcR/CD3 complex is required for the peripheral representation of certain T cell types.