Objective: Osteoporosis is a complex health disease characterized by low bone mineral density (BMD), which is determined by an interaction of genetics with metabolic and environmental factors. The tumor necrosis factor receptor superfamily, member 11b (TNFRSF11B) gene, has been investigated in relation to BMD. Three polymorphisms in/nearby TNFRSF11B have been associated with BMD variations in some populations. The aim of this study was to investigate the possible association among three SNPs of TNFRSF11B and their haplotypes with the presence of BMD variations in postmenopausal Mexican Mestizo women. Subjects and methods: One thousand unrelated postmenopausal women of Mexican-Mestizo ethnic origin, who attended the outpatient clinic for routine, general medical evaluation, were invited and 750 women accepted to participate in the study. A structured questionnaire for risk factors was applied and BMD was measured in total hip and lumbar spine by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Three single-nucleotide polymorphisms in TNFRSF11B gene were studied: rs4355801, rs2073618, and rs6993813. Real-time PCR allelic discrimination was used for genotyping. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r 2, and haplotype analysis was conducted. Results: Of the subjects, 31% had osteoporosis, 45.1% had osteopenia, and 23.9% had normal BMD. Genotype and allele distributions showed no significant differences; however, A-G-T haplotype was associated with variations in femoral neck BMD (P = 0.022). Conclusions: In our study population, analysis of the haplotypes of TNFRSF11B is a better genetic marker for variations in BMD. © 2011 Elsevier Ireland Ltd. All rights reserved.