Bone mass and its mineral content are under genetic control. The vitamin D receptor (VDR) gene has been shown to be a major locus for genetic effects on bone mineral density (BMD), and polymorphisms in this gene accounted for a large proportion of genetic variance in BMD in an Australian population. In this study, we investigated whether similar associations are present in a North American population. We studied 139 normal healthy women (age 53.2 ± 14.5, mean ± SD) and 43 severely osteoporotic postmenopausal women (age 65.8 ± 5.9). In the 127 of them with complete genetic studies, the distribution of genotypes, determined by polymerase chain reaction on leukocyte DNA samples, agreed closely with that in the Australian population. BMD was strongly related to age and weight, and, thus was adjusted for these parameters prior to genetic analysis. We found that age modulated the effect of VDR genotypes on femoral neck BMD (FN-BMD) (TaqI, p = 0.036;BsmI, p = 0.118; ApaI, p = 0.041) such that the effect of genotype was greatest among younger (premenopausal) women and declined with age so that there was no discernible difference by age 70. Among the younger women, a high FN-BMD was associated with the TT (or aa or bb) genotype while low FN-BMD was associated with the tt (or AA or BB) genotype. In osteoporotic women, although the difference in FN-BMD between alternate TaqI homozygotes (TT vs. tt) was 0.13 g/cm2 (or about 18%), the overall difference among the genotype groups was not significant (TaqI, p = 0.13; BsmI, p = 0.21; ApaI, p = 0.09), possibly due to the small sample of osteoporotic women. There was no relationship of VDR genotype to lumbar spine BMD. We conclude that the VDR gene modulates differences in BMD in premenopausal women. Subsequent interaction of the gene and environmental factors and the role of VDR genotypes in predisposing to osteoporosis needs further study.