Objective To investigate the histopathological changes of calcitonin peptide-transfected bone marrow mesenchymal stem cells (BMSCs) combined with bone transplantation in the treatment of osteonecrosis of the femoral head (ONFH) in rabbit model. Methods The osteonecrosis models on one side femoral head of rabbits were established by liquid nitrogen. Forty-eight rabbit ONFH models were randomly divided into 3 groups. In human calcitonin gene-related peptide α (hCGRPα)-transfected BMSCs group (A), the BMSCs transfected with hCGRPα in combination with autologous bone graft were implanted into the femoral head. In empty plasmid group (B), the BMSCs transfected with empty plasmid (only pLNCX2 plasmid) and autologous bone graft were implanted. In irrelated sequence group (C), BMSCs transfected with irrelated gene [only pLNCX2-green fluorescent protein (GFP)] and autologous bone graft were implanted. Animals were sacrificed at 3rd and 6th month respectively to observe the histopathological changes in the femoral heads of rabbits. Results At 3rd month, the bone trabecular area fraction respectively was (40.89±1.12)%, (36.12±1.17)%, (36.33±1.53)% and (42.11±1.91)% in groups A, B and C and normal femoral head. The percentage of empty osteocyte lacunae respectively was (11.34±1.58)%, (16.33±1.45)%, (17.21±1.23)% and (10.47±1.41)% in groups A, B and C and normal femoral head. In group A, there were proliferation and growth of a large number of osteocytes, more mature bone trabeculae and higher area fraction, less empty osteocyte lacunae, and stronger biomechanical strength in the femoral head, which were nearly close to those in the normal control group and obviously superior to those in groups B and C. In groups B and C, there were thin and irregular bone trabeculae, more empty osteocyte lacunae, lower area fraction and imperfect bone repair. At 6th month, the bone trabeculae were mature, densification and satiation, and neatly arranged rules were seen in the femoral head of group A. The area fraction of bone trabeculae and the number of empty bone lacunae in group A were superior to those in groups B and C. Conclusion The implantation of hCGRPα-transfected BMSCs combined with autologous bone graft into the femoral head of ONFH animal models can significantly promote cells proliferation, accelerate osteogenesis, enhance bone tissue repair, and obtain good effect in the treatment of ONFH. Key words: Calcitonin gene related peptide; Bone marrow mesenchymal stem cells; Osteonecrosis of the femoral head necrosis; Model, animal