The 825C>T polymorphism of the G-protein beta3-subunit gene (GNB3) has been associated with hypertension, although results are not entirely consistent. In a sample of 282 female Caucasian dizygotic twins aged 21-80 years, we aimed to investigate the associations between blood pressure and five single nucleotide polymorphisms (SNPs) including the 825C>T and haplotypes of the GNB3 gene. The polymorphisms (-350A>G, 657A>T, 814G>A, 825C>T and 1429C>T) were genotyped by polymerase chain reaction-restriction enzyme assays. Regular association tests did not show a significant effect on blood pressure for any of the five SNPs. However, strongly significant interactions between the -350A>G, 825C>T and 1429C>T loci and adiposity (both body mass index and waist circumference) were observed for systolic blood pressure (Ps < 0.01) as well as diastolic blood pressure (Ps < 0.05), suggesting increases in adiposity amplify the effects of the SNPs on blood pressure. Haplotype analyses confirmed the effects of the GNB3 gene-obesity interaction on hypertension risk. Additionally, sib-transmission disequilibrium tests (sib-TDTs) showed significant associations with blood pressure for the 825C>T and 1429C>T loci. In summary, the presence of obesity reveals an association between blood pressure and the GNB3 gene in White females. Our data suggest that adiposity is a final pathway through which gene-lifestyle interactions may exert their effects on the development of hypertension. Our results from the combined SNP, haplotype and sib-TDT analyses also support the hypothesis that the 825C>T is a susceptibility locus for hypertension, whereas effects of other loci on blood pressure may result from their strong linkage disequilibrium with the 825C>T locus.