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Purpose: To investigate the association between the single nucleotide polymorphisms (SNPs) of the adiponectin gene and nonalcoholic fatty liver disease (NAFLD) as well as the impact of the interaction of multiple SNPs on NAFLD risk, based on a Chinese population study., Methods: A total of 612 subjects (411 male, 201 female) were selected, including 302 NAFLD patients and 310 controls. Three SNPs were selected for genotyping in the case-control study: rs266729, rs822393, and rs1501299. A logistic regression model was used to examine the interaction between the SNPs and NAFLD. The odds ratio (OR) and 95 % confidence interval (95 % CI) were calculated. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the interaction among SNPs., Results: Logistic analysis showed a significant association between genotypes of variants in rs266729 and rs822393 and increased NAFLD risk. The carriers of the homozygous mutant of two SNP polymorphisms revealed increased NAFLD risk compared to those with wild-type homozygotes; ORs (95 % CI) were 1.31 (1.14-1.81) (p = 0.001) and 1.18 (1.05-1.71) (p = 0.005), respectively. There was a significant two-locus model (p = 0.0010) involving rs266729 and rs822393, indicating a potential gene-gene interaction between rs266729 and rs822393. Overall, the two-locus models had a cross-validation consistency of 10 and testing accuracy of 62.17 %. Subjects with the CG or GG and CT or TT genotype have the highest NAFLD risk compared to subjects with the CC-CC genotype; the OR (95 % CI) was 2.52 (1.31-3.82), p < 0.001, after covariate adjustment., Conclusions: Our results support an important association of the rs266729 (-11377 G/C) and rs822393 (-4522 C/T) polymorphism with increased risk of NAFLD. The interaction analysis showed a combined effect of rs266729 and rs822393 on NAFLD.