The finding that the link between polymorphism at the vitamin D receptor (VDR) gene and rates of bone loss from the femoral neck in postmenopausal women is enhanced at low calcium intakes suggests that intestinal calcium absorption is a site of differential action of the VDR alleles. 1,25-Dihydroxyvitamin D [1,25-(OH)2D] and its receptor mediate active calcium transport, the major mechanism of calcium absorption at low calcium intakes. We compared fractional calcium absorption in healthy late postmenopausal women with (bb) and without (BB) the BSM-1 restriction site. In 60 women (26 BB and 34 bb), we measured calcium absorption and plasma 1,25-(OH)2D after 2 weeks on a high (1500 mg/day) and 2 weeks on a low (< 300 mg/day) calcium intake. The mean 45Ca absorption indexes were similar in the two groups on the high calcium intake [19.01 +/- 1.12% (+/- SEM)/L in BB and 20.45 +/- 0.97%/L in bb; P = 0.346] and differed significantly on the low calcium intake (20.57 +/- 1.10%/L vs. 23.66 +/- 0.95%/L; P = 0.044). Calcium restriction induced similar percent increases in plasma 1,25-(OH)2D, but the BB group had a smaller increase in the fractional 45Ca absorption index [7.8 +/- 3.8% (+/- SEM) vs. 20.7 +/- 3.3% in bb; P = 0.016; increments adjusted for initial absorption value]. In conclusion, compared to women with the bb variants, women with BB allelic variants of the VDR have reduced calcium absorption efficiency on low calcium intake, consistent with a functional defect in the intestinal VDR. The impact of this heritable difference is reduced at higher calcium intakes.