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The X-linked hypophosphatemia (Hyp) mutation in the mouse, a model for X-linked familial hypophosphatemic rickets in man, is characterized by defective phosphate transport. The role of vitamin D3 in the defective phosphate transport was investigated in three experiments by treatment of mutant mice with the natural hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3, or its potent synthetic analog, 1 alpha-hydroxyvitamin D3. The results showed that both compounds were able to increase urinary phosphate conservation and improve rachitic bone morphology. Only 1 alpha-hydroxyvitamin D3, however, repaired the critically important hypophosphatemia and significantly increased intestinal transport of phosphate. These results indicate that defective phosphate transport in genetic hypophosphatemia is amenable to effective treatment. We hypothesize that the intestinal phosphate transport system is not genetically deleted but, instead, is unable to respond to 1,25-dihydroxyvitamin D3. Elucidation of the mechanism whereby 1 alpha-hydroxyvitamin D3 is able to stimulate the defective phosphate transport may provide fresh insight into the metabolic basis of the disease.