The TNFRSF1B gene, which encodes the p75 TNF receptor, is a strong functional and positional candidate gene for susceptibility to osteoporosis. In a previous study, we reported that polymorphic variation in the 3' untranslated region of TNFRSF1B was associated with femoral neck bone mineral density (BMD) in a population-based cohort of Scottish women. In order to further explore the role of TNFRSF1B as a candidate gene for osteoporosis, we have now studied the relationship between a promoter polymorphism in the TNFRSF1B gene and BMD, and determined whether this polymorphism interacts with other polymorphisms in TNFRSF1B to regulate bone mass, bone loss, and osteoporotic fracture. Analysis of individual polymorphisms showed weak associations between the G593A, T598G and T620C polymorphisms and femoral neck BMD (P=0.05-0.017). On haplotype analysis, the only significant association we observed was with FN BMD when haplotypes were grouped according to presence or absence of A593-T598-C620 alleles in the 3' UTR (0.897+/-0.005 versus 0.841+/-0.01; P<0.0001). These data show that allelic variation within the TNFRSF1B gene contributes to the genetic regulation of FN-BMD and show that it is the ATC haplotype in the 3'UTR region of the gene, rather than other polymorphic variants, that seem to be responsible for the effects observed.