The genetic influence on bone mineral density (BMD) is thought to be mediated in part by alleles at the vitamin D receptor (VDR) locus. In order to assess the effect of VDR on BMD in premenopausal women, we studied 470 healthy white subjects, aged 44-50 years, participating in the Women's Healthy Lifestyle Project. Each participant was genotyped for the BsmI polymorphism at the VDR gene locus. BMD at the lumbar spine, hip and whole-body, and the whole-body soft tissue composition, were measured cross-sectionally using a Hologic QDR 2000 densitometer. The presence of a polymorphic restriction site at the VDR gene locus was specified as b, whereas absence of this site was B. The frequency distribution of the VDR genotype was: bb, 20.6%; Bb, 39.1%; and BB, 40.2%. Spinal BMD (mean +/- SD) was significantly lower in women with VDR genotype BB (1.038 +/- 0.11 g/cm2) as compared with those with genotype bb (1.069 +/- 0.12 g/cm2, p < 0.05). Trochanter BMD was 2.7% lower in those with genotype BB versus bb (0.685 +/- 0.10 g/cm2 vs 0.708 +/- 0.09 g/cm2). A similar trend was shown at each subregion of the hip, but not at the whole-body. In premenopausal women, allelic status at the VDR locus contributed to variations in spinal and trochanteric BMDs, but the absolute difference in BMDs was small, amounting to 0.26 and 0.23 standard deviations, respectively. It is concluded that in this population of healthy premenopausal women there was a significant association between polymorphisms at the VDR gene locus and both spinal and trochanteric BMDs, yet no association was demonstrated for the whole-body BMD.