There are two immunogenic sites on the type A influenza A/Japan/57 (H2N2) hemagglutinin (HA) that can be recognized by class I major histocompatibility complex (MHC), H-2Kd-restricted cytolytic T lymphocytes (CTLs). One of these sites encompasses two distinct partially overlapping epitopes, which span HA residues 204-212 and 210-219. During the analysis of the fine specificity of CTL clones directed to the HA 210-219 epitope, we found that one clone 40-2 also recognized the myeloma cell line P3x63-Ag8. P3x63-Ag8 is derived from the MOPC 21 myeloma and expresses an immunoglobulin (Ig) heavy chain variable region (VH) gene which is a member of the murine 7183 VH gene family. Recognition was specific for the endogenously processed MOPC 21 heavy chain in association with the Kd molecules, since the SP2/0 derivative of P3x63-Ag8, which does not make a functional Ig H chain, is not recognized. The VH epitope recognized by clone 40-2 could be mapped to a 10 amino acid peptide spanning MOPC 21 VH residues 49-58. Cross-reactivity for the VH gene product was also demonstrable in some heterogeneous populations of CTL generated in response to influenza virus infection. These results represent the first demonstration of cross-reactivity for an endogenously processed product of a self-Ig by the CTL directed to a foreign antigen and raise the possibility that the Ig VH expression may regulate the CD8+ T cell response to foreign antigens.