CBA (H-2k) mouse-derived lymphochoriomeningitis virus and herpes simplex virus-specific cytotoxic T lymphocytes lyse virus-infected target cells compatible on either the H-2k or H-2D region. In contrast, CBA, C3H and AKR (H-2k) mouse-derived sendai virus-specific cytotoxic T lymphocytes (CTL) fail to lyse H-2D-compatible virus-infected cells. A similar lack of H-2D region-associated lytic activity was found with C57BL/6 and C57BL/10 (H-2b) mice as well as with the recombinants B10.A (2R) [Kb-Db] and B10.A (4R) [Kk-Db]. On the other hand, BALB/c (H-2d) mice and A/J (H-2a) mice do generate H-2Dd-associated sendai virus-specific CTL. These results are in contrast to those obtained with (CBA X BALB/c)F1 and B10.HTT [Ks-Dd] mice, which failed to mount Dd region-associated CTL responses. It is concluded that D region-associated sendai virus-specific CTL responsiveness varies with the H-2 genotype of the responder cells.