The H-2U allele has been identified by others as the sole Ir gene in the H-2 ~ haplotype for the cytotoxic T lymphocyte (CTL) response to mouse lymphocytic choriomeningitis virus (LCMV). The BALB/c-H-2 em2 (C-H-2 dm2) mutant lacks H-2IJ, and thus should be ideal for assessing the contribution of virus-immune CTL to LCM immunopathology. Comparison of the C-H-2 era2 mice with congenic BALB/c mice revealed that there is a delay of about 24 h in the onset of severe inflammatory process and symptoms in the mutant strain, but the absence of H-21J did not prevent the later development of fatal disease in mice injected intracerebrally (i.c.) with neurotropic LCMV. This could indicate that virus-immune CTL are not the major mediators of clinical LCM. Spleen cells from LCMV-primed BALB/c mice did not show CTL activity for LCMVinfected C3H.OH, C-H-2 d"2, or (CBA x C-H-2dm2)F1 target cells. However, immune lymphocytes from both the mutant and the F 1 strains lyse virus-infected BALB/c cells. Furthermore, B10.HTG and, in some experiments, B10.A(5R) mice generated CTL lyric for LCMV-infected BALB/c, C=H-2 am2, and (CBA x C-H-2d~Z)F1 macrophages. Apparently H-2IJ is immunodominant in the H-2 drestricted response to LCMV. However, in the absence of H-2U, it seems that H-2K d and, to a lesser extent, H-2D d also serve as lr genes for the CTL response in this infection. Even so, the absence of the H-2Ld-restricting element results in a disease process which is either delayed in onset or less severe.