Human muscle precursor cell (hMPC) transplantation is a potential therapy for severe muscle trauma or myopathies. Some previous studies demonstrated that 1,25-dihydroxyvitamin-D3 (1,25-D3) acted directly on myoblasts, regulating their proliferation and fusion. 1,25-D3 is also involved in apoptosis modulation of other cell types and may thus contribute to protect the transplanted hMPCs. We have therefore investigated whether 1,25-D3 could improve the hMPC graft success. The 1,25-D3 effects on hMPC proliferation, fusion, and survival were initially monitored in vitro. hMPCs were also grafted in the tibialis anterior of SCID mice treated or not with 1,25-D3 to determine its in vivo effect. Graft success, proliferation, and viability of transplanted hMPCs were evaluated. 1,25-D3 enhanced proliferation and fusion of hMPCs in vitro and in vivo. However, 1,25-D3 did not protect hMPCs from various proapoptotic factors (in vitro) or during the early posttransplantation period. 1,25-D3 enhanced hMPC graft success because the number of muscle fibers expressing human dystrophin was significantly increased in the TA sections of 1,25-D3-treated mice (166.75 +/- 20.64) compared to the control mice (97.5 +/- 16.58). This result could be partly attributed to the improvement of the proliferation and differentiation of hMPCs in the presence of 1,25-D3. Thus, 1,25-D3 administration could improve the clinical potential of hMPC transplantation currently developed for muscle trauma or myopathies.