Cytotoxic effector cells were generated in human mixed lymphocyte cultures (MLCs) between cell donors differing at the HLA-D/DR region but not at HLA-A,B(C). These cells killed Epstein-Barr virus-infected lymphoblasts (EBV blasts) from donors sharing the HLA-D/DR determinants with the normal MLC-stimulating cells, but not phytohaemagglutinin (PHA) lymphoblasts from the same donors. Because EBV blasts are derived from B cells and express HLA-D/DR antigens, the most likely interpretation of these findings is that the HLA-D/ DR antigens may, by themselves, act as targets for cell-mediated cytotoxicity. © 1979 by The Williams & Wilkins Co.