The MHC-matched, minor histocompatibility Ag (miHA)-mismatched B10. BR→ CBA strain combination has been used to elucidate the immunobiology of graft-vs-host disease (GVHD) following allogeneic bone marrow transplantation. Studies conducted in the 1980s had established that B10. BR CD8+ T cells were capable of mediating GVHD in the absence of CD4+ T cells, and that CD4+ T cells were unable to induce lethal disease. In more recent studies with this GVHD model, we detected etiological discrepancies with the previously published results, which suggested that genetic drift might have occurred within the B10. BR strain. In particular, there was increased allorecognition of CBA miHA by B10. BR CD4+ T cells, as determined by both TCR Vβ spectratype analysis and the induction of lethal GVHD in CBA recipients. Additionally, alloreactivity was observed between the genetically drifted mice (B10. BR/Jdrif) and mice rederived from frozen embryos of the original strain (B10. BR/Jrep) using Vβ spectratype analysis and IFN-γ ELISPOT assays, suggesting that new miHA differences had arisen between the mice. Furthermore, T cell-depleted B10. BR/Jdrif bone marrow cells were unable to provide long-term survival following either allogeneic or syngeneic bone marrow transplantation. Gene expression analysis revealed several genes involved in hematopoiesis that were overexpressed in the lineage-negative fraction of B10. BR/Jdrif bone marrow, as compared with B10. BR/Jrep mice. Taken together, these results suggest that genetic drift in the B10. BR strain has significantly impacted the immune alloreactive response in the GVHD model by causing altered expression of miHA and diminished capacity for survival following transplantation into lethally irradiated recipients.