Background Estrogen might play an important role in type 2 diabetes mellitus pathogenesis. A number of polymorphisms have been reported in the estrogen receptor alpha (ERα) gene (also named ESR1), including the XbaI and PvuⅡ restriction enzyme polymorphisms of ESR1, which may be involved in disease pathogenesis. The aim of this study was to determine whether ERα gene polymorphisms are associated with type 2 diabetes mellitus and serum lipid level.Methods Two hundred and ninety-nine patients with type 2 diabetes mellitus were compared with three hundred and forty-one health controls of Guangzhou in China, both were male and postmenopausal female residents at 51-70 years. ESR1 genotyping was performed using polymerase chain reaction (PCR) and PvuⅡ and XbaI restriction fragment length polymorphism (PCR-RFLP) analysis.Results ESR1 allelic frequencies of P, p and X, x alleles were 0.408, 0.592; 0.360, 0.640 in the type 2 diabetes mellitus group and 0.318, 0.682; 0.328, 0.672 in the control group, respectively. In case-control study, there was significant difference in PvuⅡ, but not XbaI, allele frequency between the type 2 diabetes mellitus and control groups (P=0.001 and P=0.122). When the group was separated into men and women, the difference was significant in women (P＜0.001) but not in men (P=0.854) with the PvuⅡ genotype, and the effect of PvuⅡ variant on the development of type 2 diabetes mellitus was improved with aging. In addition, PvuⅡ genotype was associated with blood glucose [fasting blood glucose (FBG), postprandial blood glucose (PBG)] and serum lipid [total cholesterol (TC) and low density lipoprotein (LDL)-c] concentration in healthy women.Conclusions PvuⅡ polymorphism of ESR1 increases susceptibility to type 2 diabetes mellitus in Chinese Guangzhou women. ESR1 variants may also impact serum lipid metabolism, which might provide a mechanism connecting ESR1 to type 2 diabetes.