The estrogen receptor β (ERβ) mediates the action of estrogen on metabolism of lipids and lipoprotein. Therefore, its gene is a promising candidate gene for cardiovascular disease. The aim of the present study was to investigate whether the ERβ A1730G polymorphism modifies the metabolic response to hormone replacement therapy (HRT) in postmenopausal women. The population included 60 normolipidemic postmenopausal women with equal numbers of each A1730G genotype followed during a 90-day experimental period. All subjects received oral estrogen together with a progestin therapy during the HRT. ABCA1 gene expression and serum lipid and lipoprotein concentrations were measured at the beginning and end of the HRT trial. At baseline, ABCA1 gene expression, lipid or lipoprotein concentrations were not significantly different among the ERβ A1730G genotype groups. After HRT, however, subjects with GG genotype had a greater increase in ABCA1 gene expression (p = 0.002) and a trend toward greater increase in apoA-I (p = 0.058) than subjects carrying the A allele. An interaction effect between genotype and HRT effect was observed on ABCA1 gene expression. In conclusion, the positive changes of ABCA1 gene expression and apoA-I were affected by the ERβ A1730G polymorphism in women taking estrogen-progesterone therapy.