Background -1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and parathyroid hormone (PTH) are major regulators of calcium homeostasis. Here, we investigated the importance of 1,25(OH)2D3-mediated renal calcium reabsorption for calcium and bone homeostasis in response to normal or low dietary calcium supply. Methods - The vitamin D receptor (VDR) was deleted in renal tubules using inducible Pax8-Cre mice starting from 3 weeks of age (VdrRen- mice). Mice were weaned on diets containing either 1% or 0.2% calcium and examined at the age of 8 weeks. Results - Male and female VdrRen- mice on normal diet showed increased urinary calcium excretion, which was accompanied by a 50% reduction in S100g renal transcript levels. Yet, VdrRen- mice were normocalcemic, indicating compensation by other calcium-regulating systems. Transcript levels of Trpv6, S100g, and Pmca1 were significantly increased in duodenum of male VdrRen- mice, whereas only a marginal increase was observed in female mice. Microcomputed tomography analysis revealed that bone mass was slightly lower in male and female VdrRen- mice, despite normal serum PTH levels. Feeding a low calcium diet had no additional effect on urinary calcium excretion and mice remained normocalcemic. However, we noted a sex-specific change in gene expression of intestinal calcium transporters, with increased levels in duodenum and colon of male VdrRen+ mice that were further enhanced in VdrRen- mice. Female mice on the low calcium diet showed increased gene expression of calcium transporters, but only in the colon and no differences between genotypes were observed. Trabecular bone mass tended to decrease more in VdrRen- (52%) than in VdrRen+ mice (40-42%) in both genders when mice were fed the low calcium diet. Serum PTH levels increased in male and female VdrRen+ mice, and in female but not male VdrRen- mice. Conclusion - Vdr deletion in renal tubules increased calcium excretion without affecting serum calcium levels, likely because of increased intestinal calcium absorption. Feeding a low calcium diet increased the expression of intestinal calcium transporters in male and female VdrRen+ mice, and this induction was significantly enhanced in male VdrRen- mice but not in females, indicating a sexually dimorphic compensation of intestinal calcium absorption in response to absent renal Vdr signaling. Regardless of the diet, bone mass was slightly lower in VdrRen- mice, illustrating that renal calcium reabsorption has a small impact on bone homeostasis. Taken together, intestinal calcium absorption compensates for the loss of renal VDR-mediated calcium reabsorption in male but not female mice.