Objective: To explore whether p53 heterozygote could attenuate osteoporosis phenotype of 1,25(OH)2D3 deficiency mice by enhancing the antioxidant capacity. Methods: The long bones of 10-week-old p53 heterozygote (p53+/-) mice, 1α-hydroxylase knockout (1α(OH)ase-/-) mice, 1α(OH)ase-/-p53+/- mice and WT (wild type, WT) littermates fed on a high calcium and phosphorus diet were analyzed and compared each other using x-ray, CT, histopathological and molecular techniquesto observe phenotype and alterations of bone density, bone formation, bone absorption and oxidative stress of these mice. Results: Compared with WT littermates, serum levels of calcium, phosphorus, parathyroid hormone (PTH) and 1,25(OH)2D3 were not altered in p53+/- mice. Bone density, total collagen (T-col) positive area, the number of osteoblast, alkaline phosphatase (ALP) and collagen type I (Col-Ⅰ) positive area were increased slightly in p53+/- mice. ROS levels were decreased, and SOD1 protein expression levels were increased in p53+/- mice. In 1α(OH)ase-/- and 1α(OH)ase-/-p53+/- mice, serum levels of calcium, phosphorus and PTH levels were normal and 1,25(OH)2D3 levels were undetectable. Compared with 1α(OH)ase-/- mice, bone density, T-col positive area, the number of osteoblast, ALP positive area and Col-I positive area of 1α(OH)ase-/-p53+/- mice were increased clearly. The number of osteoclast and ROS levels were decreased while SOD1 protein expression levels were increased in 1α(OH)ase-/-p53+/- mice. Conclusion: p53 heterozygote can attenuate osteoporosis phenotype of 1,25(OH)2D3 deficiency mice by enhancing the antioxidant capacity.