Osteopontin (OPN) is an extracellular matrix protein that is expressed in bone cells such as osteoblast and osteocytes and associated with bone turnover and bone mineral density (BMD) in postmenopausal women. Here, we aimed to investigate the relationship between circulating OPN levels and BMD in postmenopausal women in Southern China. A total of 362 postmenopausal women were consecutively recruited into this study from 2011-2013. Serum levels of OPN, receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL), and bone turnover markers were analyzed. BMD was measured by dual energy X-ray absorptiometry. Osteoporosis and osteopenia were diagnosed according to the World Health Organization criteria. Serum OPN levels were remarkably higher in the osteoporotic group than those in the osteopenic and normal groups (all p < 0.001). The cut-off value of OPN for diagnosing postmenopausal osteoporosis was 10.1 ng/mL, which had a sensitivity of 89.5%, a specificity of 70.8%, and an area under curve of 0.953. Serum OPN was negatively correlated with parathyroid hormone (PTH), lumbar spine BMD, and femoral neck BMD (r = -0.25, p = 0.004; r = -0.66, p < 0.001; r = -0.28, p = 0.001; respectively) and positively associated with type I procollagen amino-terminal propeptide (PINP), carboxy-terminal cross-linking telopeptide of type I collagen (CTX), and RANKL (r = 0.20, p = 0.020; r = 0.17, p = 0.036; r = 0.19, p = 0.028, respectively) in the osteoporotic group. In multiple regression analyses, lumbar spine BMD, PTH and RANKL were the predictors for serum OPN levels. In conclusion, OPN serum levels are negatively related to BMD and positively correlated with bone turnover levels in this group of Chinese postmenopausal women.