Mixed allogeneically reconstituted mice (B10 + B10.D2----B10) that specifically accept B10.D2 tail skin allografts were examined for in vivo and in vitro immunocompetence, patterns of hematopoietic repopulation, and in vitro reactivity. In vitro, mixed allogeneic chimeras (B10 + B10.D2----B10) manifested specific tolerance in mixed lymphocyte reactions and cell-mediated lympholysis to B10 and B10.D2 splenocytes, with normal responses to third-party (B10.BR) cells. Such chimeras were immunocompetent in B cell and helper T cell responses, as assessed by their primary plaque forming cell responses to in vivo sheep red blood cell immunization. This is in contrast to fully allogeneic chimeras, which responded less well. In addition, survival of the mixed allogeneic chimeras in a conventional animal facility was superior to that of fully allogeneic chimeras, and similar to syngeneically reconstituted (B10----B10) mice. Specific tolerance to skin grafts, degree of allogeneic engraftment, and persistence of chimerism was also assessed in a noncongenic mixed allogeneic combination (B10 + C3H----B10). Such animals manifested specific hyporeactivity to C3H skin allografts, but eventual chronic rejection of the grafts occurred in spite of stable and persistent mixed chimerism. MHC-congenic (B10.BR) skin grafts were accepted indefinitely in the same animals, suggesting that skin-specific non-major histocompatibility complex antigens were responsible for rejection of the C3H skin allografts.