AbstractX‐linked hypophosphatemia is a genetic bone disease in humans and mice. Two closely linked mutations in mice.HypandGy. cause low plasma phosphate and a rachitic and osteomalacic bone disease. Because of the controversy as to whetherGyis a good model for X‐linked hypophosphatemia, the phenotypic severity of these two mutations was compared in both sexes and on two genetic backgrounds. The depression in plasma levels of phosphate was similar in all 10‐week‐old mutant mice. MaleHypmice and heterozygous femaleHypmice were affected with similar severity in terms of reduced tail growth, shortened femora, reduced femoral mineral content, and abnormal mineral composition of the femoral matrix. In contrast, maleGymice did not survive on the C57BL/6J background and were more severely affected than femaleGymice on the B6C3H background. The hybrid B6C3H background ameliorated the bone disease compared with the inbred C57BL/6J background for both mutant strains. There was no evidence of change in the plasma levels of 1.25‐dihydroxyvitamin D, duodenal level of vitamin D‐dependent calcium‐binding protein, or urinary level of calcium in these adult mutant mice. In summary,Gymice have a sexual dimorphism not present inHypmice. These two genes may indicate the presence of multiple gene loci in the human disease, with multiple proteins involved in the pathophysiology of the