Purpose:　Osteonecrosis　of　the　femoral　head　may　be　a　disease　resulting　from　abnormal　proliferation　or　differentiation　of　mesenchymal　stem　cells.　The　present　investigation　explored　the　novel　strategy　of　hypoxia-preconditioned　BMMSCs　to　reverse　the　impairment　of　osteonecrosis　BMMSCs　and　enhance　the　therapeutic　potential　of　hypoxia-treated　BMMSC　transplantation.　Methods:　BMMSCs　from　the　anterior　superior　iliac　spine　region　of　osteonecrosis　rabbit　were　cultured　under　20%　O-2　or　2%　O-2　conditions.　Normal　BMMSCs　were　cultured　under　20%　O-2　condition　as　control.　Growth　factors　secreted　were　examined　by　enzyme-linked　immunosorbent　assay.　20%　O-2　or　2%　O-2　BMMSCs　were　injected　into　the　femoral　head　of　rabbits　after　core　decompression.　Cell　viability　and　apoptosis　were　assessed　in　vitro,　and　TUNEL　staining　of　the　femoral　head　was　analyzed　after　transplantation.　Angiogenesis　(capillary-like　structure　formation,　CD31　immunohistochemical　staining　and　ink　infusion　angiography)　and　osteogenesis　(Alizarin　red-S　staining,　micro-CT　scanning　and　OCN　immunohistochemical　staining)　tests　were　conducted　as　well.　Results:　2%　O-2　exposure　up-regulated　growth　factor　secretion　in　BMMSCs.　Apoptosis　in　2%　O-2　group　was　lower　when　compared　with　that　in　20%　O-2　osteonecrosis　group.　Cell　viability　in　2%　O-2　was　significantly　higher　when　compared　with　that　in　20%　O-2　osteonecrosis　group.　Growth　factor　secretion,　cell　viability,　apoptosis,　capillary-like　structure　formation,　Alizarin　red-S　staining,　and　ALP　staining　showed　no　difference　between　the　2%　O-2　BMMSC　and　normal　BMMSC　groups.　Transplantation　of　2%　O-2　versus　20%　O-2　mesenchymal　stem　cells　after　core　decompression　resulted　in　an　increase　in　angiogenesis　function　and　a　decrease　in　local　tissue　apoptosis.　Our　study　also　found　that　osteogenesis　function　was　improved　after　hypoxic　stem　cell　transplantation.　Conclusion:　Hypoxic　preconditioning　of　BMMSCs　is　an　effective　means　of　reversing　the　impairment　of　osteonecrosis　BMMSCs,　promoting　their　regenerative　capability　and　therapeutic　potential　for　the　treatment　of　osteonecrosis.　(C)　2015　Elsevier　Inc.　All　rights　reserved.