AbstractX‐linked hypophosphatemic (Hyp) mice are a model for human sex‐linked vitamin D‐resistant rickets. We have reported intestinal malabsorption of calcium in youngHypmice, and in this report we have explored the mechanism for it. To test for resistance of the intestine to 1,25(OH)2vitamin D3, this hormone was continually infused via osmotic minipumps into 4‐week‐old normal andHypmice at 0,17, 50 or 150 ng/kg/day. After 3 days,45Ca and inorganic32P were administered by gavage, and the mice were sacrificed on the fifth day. TheHypmice showed responses to the hormone equivalent to the normal mice in terms of increased intestinal absorption of both45Ca and32P, increased plasma isotope levels, increased femoral isotope content, and increased duodenal and renal 9 kD vitamin D‐dependent calcium‐binding protein (calbindin‐D9K; CaBP). Plasma 1,25(OH)2D was measured in these mice. There were significant correlations of plasma 1,25(OH)2D to the intestinal absorption of45Ca and32P and to duodenal and renal CaBP. Plasma 1,25(OH)2D was also measured in stock normal andHypmice and was found to be lower in 4‐week‐oldHypmice than in 4‐week‐old normal mice (113 ± 10 pM(n= 18) vs. 67 ± 10 (n= 20), normal vs.Hyp, p<.01), but unchanged at 13 weeks of age (77 ± 13 (n= 13) vs. 70 ± 15 (n= 15), NS). This observed difference in plasma 1,25(OH)2D between normal andHypmice at 4 weeks of age was sufficient to explain the observed normal‐to‐Hypdifferences in intestinal absorption of45Ca and duodenal and renal CaBP. It also explained 72 ± 18% of the observed difference in32P absorption. We conclude thatHypmouse intestine is not resistant to 1,25(OH)2D and that the lower plasma 1,25(OH)2D of 4‐week‐oldHypmice causes intestinal ma