Mesenchymal-stem-cell-based regenerative medicine is a promising approach for functional tissue reconstruction. A recent study showed that host immune cells regulated bone marrow mesenchymal stem cell (BMMSC)–mediated tissue regeneration. However, it is unknown whether systemic infusion of BMMSCs, which induces immune tolerance, affects cell-based tissue regeneration. In this study, we showed that BMMSCs possessed an immunomodulatory function in vitro. Moreover, systemic infusion of BMMSCs reduced IFN-γ and TNF-α levels in the implantation sites via upregulation of regulatory T cells (Tregs), resulting in marked enhancement of cell-based bone regeneration, but with only limited contribution by BMMSC homing. Further, we showed that systemic BMMSC infusion significantly improved cell-based repair of critical-sized calvarial defects in a murine model. These results suggested a new approach to enhance cell-based bone regeneration.