The dimeric cell-surface glycoprotein CD8 is crucial to the positive selection of cytotoxic T cells in the thymus(1). The homodimer CD8 alpha alpha or the heterodimer alpha beta stabilizes the interaction of the T-cell antigen receptor(TCR) with major histocompatibility complex (MHC) class I/peptide by binding to the class I molecule(2). Here we report the crystal structure at 2.7 Angstrom resolution of a complex between CD8 alpha alpha and the human MHC molecule HLA-A2, which is associated with peptide. CD8 alpha alpha binds one HLA-A2/ peptide molecule, interfacing with the alpha 2 and alpha 3 domains of HLA-A2 and also contacting beta(2)-microglobulin. A flexible loop of the alpha 3 domain (residues 223-229) is damped between the complementarity-determining region (CDR)-like loops of the two CD8 subunits in the classic manner of an antibody-antigen interaction, precluding the binding of a second MHC molecule. The position of the alpha 3 domain is different from that in uncomplexed HLA-A2 (refs 3, 4), being most similar to that in the TCR/Tax/HLA-A2 complex(5), but no conformational change extends to the MHC/peptide surface presented for TCR recognition. Although these shifts in alpha 3 may provide a synergistic modulation of affinity, the binding of CD8 to MHC is clearly consistent with an avidity-based contribution from CD8 to TCR-peptide-MHC interactions.