Clonally expressed T-cell receptor αβ heterodimers are able to bind many different major histocompatibility complex/peptide combinations. This promiscuity is thought to be required for adequate surveillance against microbial and malignancy-associated antigens. After transplantation, T cells may react with nonself structures, contributing to graft-versus-host disease, in the case of hematopoietic stem cell transplantation, or graft failure, when the host immune system is preserved. We describe 2 distinct HLA A*0201–restricted, cytotoxic CD8 T-cell responses to the prevalent chronic pathogen, herpes simplex virus type 2, that cross-react with cells bearing specific alleles of the common HLA B44 family. Transfection of human or primate renal epithelial cells with HLA class I complementary DNA confirmed these results. Given the prevalence of this viral infection and the HLA alleles involved, it is possible that this cross-reactivity may be involved in clinically significant events.