Background: Adiponectin, an adipokine facilitating insulin action, has antiatherogenic effects. This study investigated whether common single nucleotide polymorphisms (SNPs) in the adiponectin gene influenced plasma adiponectin level and whether they were associated with the risk of coronary artery disease (CAD) and its angiographical severity in type 2 diabetes in Chinese population. Methods: 11 tagging SNPs were genotyped in 1110 subjects with or without CAD in type 2 diabetes. Variants of adiponectin gene were determined by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by sandwich enzyme-linked immunosorbent assay. The severity and extent of coronary atherosclerosis were assessed using the angiographic Gensini score and Sullivan Extent score. Results: Among the 11 SNPs, the minor G allele of SNP rs266729 was significantly associated with higher odds of CAD (odds ratio (95% CI) = 1.49 (1.10 - 2.16), P = 0.022) after adjusting for covariates. In stepwise multivariate logistic regression, SNP rs266729 was a significant independent factor of CAD. Multivariate linear regression analysis revealed that rs266729 (beta = -0.101, P < 0.0001), rs182052 (beta = -0.044, P = 0.0035), and rs1501299 (beta = 0.073, P < 0.0001) were significantly associated with adiponectin level, and also indicated that the minor G allele of SNP rs266729 had higher Gensini score (beta = 0.139, P < 0.001) and Sullivan Extent score (beta = 0.107, P < 0.001). Haplotypes analysis revealed different haplotype distributions in case and control subjects (P = 0.0003), with two common haplotypes GGG and GAG of the rs266729, rs182052, and rs1501299 being associated in heterozygotes with a greater than threefold increase in cardiovascular risk (odds ratio (95% CI)= 3.39 (1.83 - 6.30), P = 0.0001). Conclusions: In our population, genetic variants in the adiponectin gene influence plasma adiponectin levels, and one of them is a strong determinant of CAD susceptibility and its angiographical severity in type 2 diabetes. This study has provided further evidence for a role of adiponectin in the development of CAD.