Bone mineral density (BMD) achieved during young adulthood (peak BMD) is one of the major determinants of osteoporotic fracture in later life. Genetic variants associated with BMD have been identified by three recent genome-wide association studies. The most significant single-nucleotide polymorphisms (SNPs) from these studies were genotyped to test whether they were associated with peak BMD in premenopausal American women. Femoral neck and lumbar spine BMD were determined by dual-energy X-ray absorptiometry in two groups of premenopausal women: 1524 white women and 512 black women. In premenopausal white women, two SNPs in the C6orf97/ESR1 region were significantly associated with BMD (p < 4.8 x 10(-4)), with suggestive evidence for CTNNBL1 and LRP5 (p < .01). Evidence of association with one of the two SNPs in the C6orf97/ESR1 region also was observed in premenopausal black women. Furthermore, SNPs in SP7 and a chromosome 4 intergenic region showed suggestive association with BMD in black women. Detailed analyses of additional SNPs in the C6orf97/ESR1 region revealed multiple genomic blocks independently associated with femoral neck and lumbar spine BMD. Findings in the three published genome-wide association studies were replicated in independent samples of premenopausal American women, suggesting that genetic variants in these genes or regions contribute to peak BMD in healthy women in various populations.