The CD8 glycoprotein is expressed by thymocytes, mature T cells and natural killer (NK) cells and has been implicated in the recognition of monomorphic determinants on major histocompatibility complex (MHC) Class I antigens, and in signal transduction during the course of T‐cell activation. Both human and rodent CD8 antigens are comprised of two distinct polypeptide chains, α and β. The majority of monoclonal antibodies (mAb) reactive with the human CD8 antigen bind the CD8α chain, while a single mAb, T8/2T8–5H7, has been identified which binds to the CD8 α/β heterodimer. While the two chains of CD8 have been presumed to be coordinately expressed in normal T cells, this is not always the case. Northern blot analysis of a panel of T‐cell leukemias and normal cells demonstrate that CD8α and CD8β are not invariably co‐transcribed and phenotypic analysis of fresh and interleukin 2 (IL‐2) expanded peripheral blood mononuclear cells (PBMC) confirm that the CD8α and CD8β chains are differentially expressed at the cell surface. Four distinct subpopulations of CD8 + cells have been identified based on the expression of CD8 α/α or CD8 α/β complexes: (1) T‐cell receptor (TcR) αβ+ T cells which are CD8 α+/β+ (2) TcR αβ+ T cells which are CD8 α+/β‐; (3) TcR γδ+ T cells which are CD8 α+/β‐ and (4) natural killer (NK) cells which are CD8 α+/β‐. We also demonstrate the down‐regulation of the CD8 α/β heterodimers from the surface of a CD8 + T‐cell clone following treatment with phorbol myristate acetate (PMA) while CD8 α/α homodimers remain on the cell surface. This observation demonstrates that a) a CD8+ T‐cell clone can express both CD8 α/α homodimers and CD8 α/β heterodimers and b) these two complexes do not have identical biological properties. Together, these data suggest that CD8 α/α and CD8 α/β dimers may not subserve identical functions. The differential contribution of these two CD8 complexes should be considered in models of T‐cell‐mediated cytotoxicity and T‐cell activation.