Objective: The purpose of the current study was to identify the association between polymorphisms +3174G/A of insulin-like growth factor-I receptor (IGF-IR) gene and c5002G/A of insulin-like growth factor-II receptor (IGF-IIR) gene and osteoporosis in postmenopausal women of Han Chinese. Materials and methods: This case-control study involved 218 patients with postmenopausal osteoporosis and 270 age-matched controls to genotype polymorphisms +3174G/A of IGF-IR and c5002G/A of IGF-IIR using restriction fragment length polymorphisms (RFLP)-polymerase chain reaction (PCR) assay. BMD values at lumbar spine, femoral neck and forearm were measured using dual-energy X-ray absorptiometry. Serum IGF-I was investigated by enzyme-linked immunosorbent assay. Results: Our data showed the distributions of AA genotype (29% vs. 17%) and A allele (51% vs. 40%) of IGF-IR gene +3174G/A polymorphism were significantly more frequent in the osteoporotic women than controls. Conditional logistic regression revealed that AA genotype of IGF-IR was statistically associated with osteoporosis (OR=2.40, 95% CI=1.46-3.95, P=0.001). After adjustment for age, menopause duration and BMI, AA genotype was still significantly associated with an increased risk of osteoporosis (OR=2.10, 95% CI=1.26-3.51, P=0.004). And osteoporotic women with AA genotype of IGF-IR were found to have a lower values of serum IGF-I and BMD at forearm and femoral neck compared with other genotype. Conclusions: Our results suggested that the IGF-IR gene +3174G/A polymorphism may affect the susceptibility to osteoporosis in postmenopausal women of Han Chinese and may change serum IGF-I level.