Osteoporosis represents an important cause of morbidity in adult rheumatoid arthritis (RA) patients who exhibit increased fracture risk. It is thought that osteoclast and its dysfunction which mediated by many cytokines are the principal pathogenesis of this bone disease, although the mechanisms are still not fully understood. Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL) have been revealed in the pathogenesis of primary osteoporosis and other metabolic bone diseases. Thus, the aim of this study was to investigate the possible role of the OPG/RANKL system in RA-related bone loss. A total of 64 Chinese patients with RA and 60 healthy control subjects were involved. Serum levels of OPG and RANKL were measured by ELISA. BMD of nondominant forearm, lumbar spine(L(1-4)) and proximal femur, including femoral neck, Wards triangle, greater trochanter were assessed using dual-energy X-ray absorptiometry. RA patients had a higher incidence of osteoporosis (23/64, 35.9%) than that in healthy controls (9/60, 15.0%) (P < 0.0001). They displayed lower BMD values than controls at positions of all detected region. Compared with healthy controls, RA group showed significantly higher serum levels of RANKL (48.4 ± 12.5 vs. 23.0 ± 11.2 pmol/l, P < 0.0001), lower serum levels of OPG (106.2 ± 40.6 vs. 231.6 ± 65.6 pg/ml, P < 0.0001), and OPG/RANKL ratio (2.4 ± 0.7 vs. 7.0 ± 1.1, P < 0.0001). Multiple linear regression analysis revealed that in RA group, plasma rheumatoid factor concentration (β = -0.187, P = 0.031), swollen joint count (β = 0.567, P = 0.029), BMD at forearm (β = 0.324, P = 0.002), femoral Wards triangle (β = 0.370, P < 0.0001), and lumbar spine (β = 0.313, P = 0.003) were the contributors for serum OPG (R ( 2 ) = 0.718, P < 0.0001). Age (β = 0.241, P = 0.042) and BMD at femoral Wards triangle (β = -0.441, P < 0.0001) and lumbar spine (β = -0.320, P = 0.013) were the determinants for serum RANKL (R ( 2 ) = 0.616, P < 0.0001), while swollen joint count (β = 1.029, P = 0.019) and BMD at femoral neck (β = 0.285, P = 0.042) for serum OPG/RANKL ratio (R ( 2 ) = 0.279, P < 0.011). Analysis of logistic regression showed age (P = 0.004, OR = 1.156, 95% CI: 1.047-1.276) and the level of C-reactive protein (P = 0.028, OR = 1.019, CI 95%: 1.002-1.036) in peripheral blood of RA were the risk factors for the occurrence of osteoporosis in RA, while OPG/RANKL ratio (P = 0.007, OR = 0.035, CI 95%: 0.003-0.400) was the unique protective factor. These data suggest that, in Chinese RA patients, an altered modulation of the OPG/RANKL system resulting in increased RANKL and decreased OPG in peripheral blood, could contribute to the bone loss characteristic and the generation of osteoporosis in these patients. Changes of ratio of OPG/RANKL might be a protective mechanism against the accelerated bone loss in RA.