Genetic and lifestyle factors are important in the pathogenesis of osteoporosis. We investigated the relationships of PvuII and XbaI polymorphisms of the estrogen receptor alpha (ER-alpha) gene, lifestyle factors with speed of sound at the calcaneus (calcaneal SOS) and osteoporosis in a population-based study of 140 healthy postmenopausal women. By an analysis of covariates, women with higher copies of P or X alleles had higher calcaneal SOS compared with others (P=0.012, PP vs. pp; P=0.045, Xx vs. xx). Women with lower copies of px or higher copies of PX haplotypes had higher calcaneal SOS compared with others (P=0.021, 0 px vs. 2 px; P=0.011, 1 PX vs. 0 PX). The px and PX haplotypes, age and years since menopause were found to be independent predictors of calcaneal SOS in multiple linear regression models. Using logistic regression, we found an increased osteoporosis risk with evidence for a px haplotype dose effect (OR=2.82, 95% CI=1.50-5.31, P=0.001) and for a PX haplotype dose effect (OR=0.42, 95% CI=0.19-0.93, P=0.033). An increased educational level was associated with a reduced risk of osteoporosis (P=0.035 in the model with px, P=0.044 in the model with PX). In conclusion, the present study suggests that PvuII and XbaI polymorphims of the ER-alpha gene, age, years since menopause and educational level are associated with bone density, as assessed by calcaneal SOS, and osteoporosis in postmenopausal Vietnamese women.