CD8 T cells that recognize cytomegalovirus (CMV) ‐encoded peptides can be readily detected by staining with human leucocyte antigen (HLA) –peptide tetramers. These cells are invariably highly differentiated effector memory cells with high avidity T‐cell receptors (TCR). In this report we demonstrate an HLA‐A*0201 restricted CMV‐specific CD8 T‐cell response (designated YVL) that represents several percent of the CD8 T‐cell subset, yet fails to bind tetrameric major histocompatibility complex (MHC) ligands. However, these tetramer‐negative cells are both phenotypically and functionally similar to other CMV‐specific CD8 T cells. YVL peptide‐specific CD8 T‐cell clones were generated and found to be of high avidity in both cytotoxicity and interferon‐γ (IFN‐γ) assays, and comparable with other CMV peptide‐specific CD8 T‐cell clones. However, under conditions of CD8 blockade, the response was almost nullified even at very high ligand concentrations. This was also the case in IFN‐γ experiments using peripheral blood mononuclear cells stimulated with peptide ex vivo. In contrast, all other CMV specificities (tetramer‐positive) displayed minimal or only partial CD8 dependence. This suggests that YVL‐specific responses depict a low‐affinity TCR–MHC–peptide interaction, that is compensated by substantial CD8 involvement for functional purposes, yet cannot engage multivalent soluble ligands for ex vivo analysis. It is interesting that such a phenomenon is apparent in the face of a persistent virus infection such as CMV, where the responding cells represent an immunodominant response in that individual and may present a highly differentiated effector phenotype.