AbstractAllogeneic irradiation bone marrow chimeras C57BL/10 (H‐2b) →B10.BR (H‐2k) and B10.BR (H‐2k)→C57BL/10 (H‐2b) were raised under specific pathogen‐free (SPF) conditions; they survived very well and were healthy under SPF for 3–4 months and subsequently, under conventional housing conditions, for 1 to 8 months. Their immune response against third‐party alloantigens was comparable with that of controls. Anti‐vaccinia virus responses were very low when compared with syngeneic control chimeras or unmanipulated control animals; if anti‐vaccinia virus cytotoxic T cell reactivity was measurable, it was specific for the bone marrow donor, rather than the recipient thymic H‐2 type. In contrast, the anti‐LCMV (lymphocytic‐choriomeningitis virus) response was excellent and comparable to that in controls for B10.BR (H‐2k)→C57BL/10 (H‐2b) chimeras, but was completely absent for C57BL/10 (H‐2b)→B10.BR (H‐2k) chimeras. LCMV‐specific cytotoxic effector T cells from B10.BR→C57BL/10 chimeras were restricted entirely to recipient H‐2b. In contrast to the asymmetric cytotoxic T cell response, both types of chimeras developed good primary footpad swelling reactions after local infection, which arose somewhat slower with LCMV than in control of chimeras. The capacity to control infection byListeria monocytogeneswas excellent for all controls and B10.BR→C57BL/10 chimeras but apparently absent in C57BL/10→B10.BR chimeras.Differentiation of T cell restriction specificity for thymic H‐2 is apparently most efficient, but it remains unclear whether the observed asymmetry reflects exaggerated immune response regulation in H‐2‐incompatible stem cell‐thymus chimeras or differential cross