While it is generally agreed that the specificity of the interaction between cytolytic T lymphocytes (CTL) and their target cells is controlled mainly by antigen-specific T cell receptors (TcR), the molecular role of cell surface CD8 molecules in this interaction is less well understood. In the present study we have reinvestigated the apparent contribution of CD8 molecules to the overall avidity of interaction between CTL and their targets by using a recently developed system of major histocompatibility complex (MHC) class I-restricted CTL clones that recognize defined peptide antigens. We demonstrate that under conditions where the density of MHC, TcR and accessory molecules remains constant, the susceptibility of CD8+ CTL to inhibition of cytolysis by anti-CD8 antibodies is highly dependent upon the concentration and primary structure of the peptide antigen. Although the precise role of the CD8 molecule remains unknown, our results are compatible with models that suggest its contribution to the overall avidity of the CTL-target cell interaction particularly in cases where the affinity between the TcR and antigen-MHC is low.