Osteoporosis is a common multifactorial disease in postmenopausal women. This study aimed to investigate the association of the g.27563G>A osteoprotegerin (OPG) genetic polymorphism with bone mineral density (BMD) and osteoporosis. A case-control study was carried out with 435 osteoporosis postmenopausal women cases and 442 age-matched healthy controls. The BMD at the femoral neck hip, lumbar spine (L₂₋₄), and total hip were assessed by Norland XR-46 dual-energy X-ray absorptiometry. The genotypes of the g.27563G>A genetic polymorphism were detected by created restriction site-polymerase chain reaction and verified by DNA sequencing methods. We detected that the g.27563G>A genetic polymorphism was a non-synonymous mutation that resulted in an arginine (Arg) to glutamine (Gln) amino acid replacement (p.Arg333Gln). Significant differences were found in the BMD of the femoral neck hip, lumbar spine (L₂₋₄), and total hip among different genotypes of the g.27563G>A genetic polymorphism. Subjects with the genotype GG had significantly higher BMD values than those with genotypes GA and AA (P < 0.05). Our data indicated that the A allele of the g.27563G>A genetic polymorphism in OPG could be associated with lower BMD values in the Chinese postmenopausal women evaluated, and that it might be an increased risk factor for osteoporosis.