The receptor for advanced glycation end products (RAGE) has been reported to relate to osteoarthritis (OA), however, the role of RAGE genetic variants in OA remains unknown.A total of 233 patients with primary knee OA and 255 healthy volunteer were recruited. Three RAGE gene polymorphisms, namely, Gly82Ser (rs2070600). -374T/A (rs1800624) and 429T/C (rs1800625) were genotyped.Of all three RAGE gene polymorphisms, only the genotype distributions and alleles frequencies of 82G/S polymorphisms significantly differed between knee OA and control subjects. The presence of SS genotype and S allele of 82G/S we significantly higher in knee OA subjects than in controls (34.76% vs. 19.61%, P for trend =0.004; 57.64% vs. 48.59%, P for trend <0.001, respectively). Multivariate logistic regression analysis showed a significantly increased risk for knee OA for the SS genotype compared with the AA genotype (OR= 1.984, 95% CI: 1.238-3.181; P =0.004). The adjusted OR for S allele carriage was significantly higher than G allele carriage (OR=1.440, 95% CI: 1.137-1.8231, P=0.002). Moreover, a significant multiplicative interaction was observed between 82G/S polymorphisms with obesity (Pinteraction=0.028). Taking the non-obese 82GG genotype as references, the OR for OA in non-obese SS carriers was 2.537 (95% CI 1.241-5.189, P=0.001). Notably, the OR in obese GS carriers was 2.304 (95% CI: 1.218-4.357, P=0.009) and in obese SS was 3.392 (95% CI: 1.672-6.885, P=0.001). The -374T/A and -429T/C did not show positive interaction with obesity and smoking status.The AGE 82G/S polymorphisms, in interaction with obesity, may determine the susceptibility of OA in Chinese population.