We evaluated the interaction effects between the estrogen receptor alpha gene (ER-alpha), vitamin D receptor gene (VDR), age and sex on bone mineral density (BMD) in a sample of 340 unrelated males and 297 unrelated females from 401 Chinese nuclear families. Polymorphisms of PvuII and XbaI in the ER-alpha gene and ApaI in the VDR gene were detected by RFLP, and ER-alpha genotype was defined by the haplotype reconstructed according to the two loci. In the females, significant ER-VDR gene interaction ( P<0.05) was found on the lumbar spine BMD. Such interaction might account for approximately 1.0% of the BMD variation. At the femoral neck and trochanter, significant ER-age interaction effects were observed, which might explain 0.3% BMD variation for both skeletal sites. In the males, significant VDR-age interaction was found on femoral neck BMD ( P<0.05), and it accounted for 0.6% BMD variation. These interaction effects were largely dependent on gender groups, suggesting there may exist ER-VDR-sex, ER-age-sex, and VDR-age-sex complex interactions in our Chinese sample.