Low bone mineral density (BMD) is one of the most important risk factors for osteoporosis. Apolipoprotein E (APOE) has been considered as a candidate gene for osteoporosis because of its influence on osteoblast uptake of lipoprotein-borne vitamin K. Using the quantitative transmission disequilibrium test QTDT, we examined linkage and/or association of APOE and BMD at the lumbar spine and the total hip in a sample of 387 Caucasian nuclear families with 715 parents and 953 children. The children were aged 20-50 years and female offspring were premenopausal as well. Four single nucleotide polymorphisms (SNP1-4) in the APOE gene, 4-locus haplotypes and 2-locus haplotypes (epsilon1, epsilon2, epsilon3, epsilon4 isoforms, reconstructed by SNP3 and SNP4) were analyzed. In the whole sample and the female offspring families we found no evidence of linkage or association for either single SNP or haplotype with BMD at the two studied skeletal sites. In the male offspring families, within-family associations were observed at the haplotypes CGTC (P = 0.001), GGTT (P = 0.002), and GATC (P = 0.006) for the lumbar spine BMD, and GATC (P = 0.008) for the total hip BMD. These data suggested that in our studied Caucasian population, APOE may have effects on BMD variation in males but not females. Further studies with a larger sample size are required to confirm such results.