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Aims: To investigate the impact of AdipoQ polymorphisms, and their additional interactions with smoking and drinking on coronary heart disease (CHD) risk based on Chinese population.Methods: Hardy‒Weinberg equilibrium (HWE) was performed using SNPStats (available online athttp://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) model was used to screen the best gene‒gene and gene‒environment interaction combinations. Logistic regression was performed to investigate association between four single-nucleotide polymorphisms (SNPs) and CHD and the interaction effect between rs1501299 and smoking.Results: Logistic analysis showed that CHD risks were higher in carriers with homozygous mutant of rs1501299 and rs2241766 than those with wild-type homozygotes, odds ratio (ORs) (95%CI) were 1.49 (1.19–1.95) and 1.71 (1.33–2.24), respectively, but CHD risks were lower in carriers with homozygous mutant of rs7649121 than those with wild-type homozygotes, OR (95%CI) was 0.72 (0.51–0.96). GMDR model indicated that there was a significant two-locus model (p= 0.0107) involving rs1501299 and current smoking, indicating a potential gene–environment interaction between rs1501299 and current smoking. Overall, the cross-validation consistency of this model was 9/10, and the testing accuracy was 60.11% (p= 0.0010). T-allele carriage had 42% prevalence, and one-quarter of them were current smokers. Smokers with rs1501299-GT or TT genotype have the highest CHD risk, compared to never-smokers with rs1501299-GG genotype, OR (95%CI) was 3.56 (1.91–5.42), after adjustment for gender, age, alcohol status, and body mass index. But we did not find any significant gene–gene and gene–drinking interaction combinations in GMDR models.Conclusions: Polymorphisms in rs1501299 and rs2241766, and their additional interactions between rs1501299 and smoking were associated with increased CHD risks: polymorphism in rs7649121 was associated with decreased CHD risks. [ABSTRACT FROM PUBLISHER]