Abstract Background Osteoporosis, a disease characterized by low bone mineral density (BMD), is an important health problem in Mexico. BMD is a highly heritable trait, with heritability estimates of 50-85%. Several candidate genes have been evaluated to identify those involved in BMD variation and the etiology of osteoporosis. This study investigated the possible association of single-nucleotide polymorphisms (SNPs) in the MEF2C , SOST and JAG1 genes with bone mineral density (BMD) variation in postmenopausal Mexican-Mestizo women. Methods Four hundred unrelated postmenopausal women were included in the study. Risk factors were recorded and BMD was measured in total hip, femoral neck and lumbar spine using dual-energy X-ray absorptiometry. In an initial stage, a total of twenty-five SNPs within or near SOST gene and seven SNPs in the JAG1 gene were genotyped using a GoldenGate assay. In a second stage, three MEF2C gene SNPs were also genotyped and SOST and JAG1 gene variants were validated. Real time PCR and TaqMan probes were used for genotyping. Results Linear regression analyses adjusted by age, body mass index and ancestry estimates, showed that five SNPs in the SOST gene were significantly associated with BMD in total hip and femoral neck but not lumbar spine. The lowest p value was 0.0012, well below the multiple–test significance threshold ( p  = 0.009), with mean effect size of -0.027 SD per risk allele. We did not find significant associations between BMD and MEF2C / JAG1 gene variants [rs1366594 “A” allele: β = 0.001 (95% CI -0.016; 0.017), P  = 0.938; rs2273061 “G” allele: β = 0.007 (95% CI -0.007; 0.023), p  = 0.409]. Conclusions SOST polymorphisms may contribute to total hip and femoral neck BMD variation in Mexican postmenopausal women. Together, these and prior findings suggest that this gene may contribute to BMD variation across populations of diverse ancestry.