Although human orofacial bone-marrow-derived mesenchymal stem cells showed differentiation traits distinctly different from those of mesenchymal stem cells (MSCs) derived from long bone marrow (BMMSCs), mouse MSCs derived from orofacial bone have not been isolated due to technical difficulties, which in turn precludes the use of mouse models to study and cure orofacial diseases. In this study, we developed techniques to isolate and expand mouse orofacial bone/bone-marrow-derived MSCs (OMSCs) from mandibles and verified their MSC characteristics by single-colony formation, multi-lineage differentiation, and in vivo tissue regeneration. Activated T-lymphocytes impaired OMSCs via the Fas/Fas ligand pathway, as occurs in BMMSCs. Furthermore, we found that OMSCs are distinct from BMMSCs with respect to regulating T-lymphocyte survival and proliferation. Analysis of our data suggests that OMSCs are a unique population of MSCs and play an important role in systemic immunity. Abbreviations: BMMSC, bone marrow mesenchymal stem cell; HA/TCP, hydroxyapatite/tricalcium phosphate; OMSC, orofacial mesenchymal stem cell; OVX, ovariectomized.