The 1p36 region of the human genome has been identified as containing a QTL for BMD in multiple studies. We analysed the TNFRSF1B gene from this region, which encodes the TNF receptor 2, in two large population-based cohorts. Our results suggest that variation in TNFRSF1B is associated with BMD. INTRODUCTION: The TNFRSF1B gene, encoding the TNF receptor 2, is a strong positional and functional candidate gene for impaired bone structure through the role that TNF has in bone cells. The aims of this study were to evaluate the role of variations in the TNFRSF1B gene on bone structure and osteoporotic fracture risk in postmenopausal women. METHODS: Six SNPs in TNFRSF1B were analysed in a cohort of 1,190 postmenopausal Australian women, three of which were also genotyped in an independent cohort of 811 UK postmenopausal women. Differences in phenotypic means for genotype groups were examined using one-way ANOVA and ANCOVA. RESULTS: Significant associations were seen for IVS1+5580A>G with BMD and QUS parameters in the Australian population (P = 0.008 - 0.034) and with hip BMD parameters in the UK population (P = 0.005 - 0.029). Significant associations were also observed between IVS1+6528G>A and hip BMD parameters in the UK cohort (P = 0.0002 - 0.003). We then combined the data from the two cohorts and observed significant associations between both IVS1+5580A>G and IVS1+6528G>A and hip BMD parameters (P = 0.002 - 0.033). CONCLUSIONS: Genetic variation in TNFRSF1B plays a role in the determination of bone structure in Caucasian postmenopausal women, possibly through effects on osteoblast and osteoclast differentiation.