Osteoporosis is a common health problem in Mexico, so it is essential to investigate the status of different gene polymorphisms that could serve as genetic susceptibility markers in the Mexican population. Genes with a role in bone metabolism are excellent candidates for association studies. In this study were determined the allelic and genotypic frequencies of four polymorphic markers (C/T rs3736228, G/A rs4988321, T/C rs627174 and T/C rs901824) in the low-density lipoprotein receptor-related protein 5 gene (LRP5) and their association with osteoporosis in 100 pos-menopausal osteoporotic Mexican women and their controls, using real time-PCR and TaqMan probes. Only the G/A polymorphism (rs4988321, Val667Met) showed significant differences (p = 0.039) when genotype frequencies were compared. However, when the haplotypes of these four polymorphisms were analyzed, interesting associations became evident. The CGTT haplotype showed significant association with low risk of osteoporosis (OR 0.629; p = 0.007; [95 % CI, 0.448-0.884]), whereas the TACT haplotype was significantly associated with a higher risk of osteoporosis (OR 7.965; p = 0.006; [95 % CI, 1.557-54.775]). Our results supported the association of LRP5 with osteoporosis and showed the potential value of LRP5 haplotypes to identify risk of osteoporosis in Mexican population.