We have recently characterized the transcriptome of the omental adipose tissue of non-diabetic, obese men with and without the metabolic syndrome (MS). The cysteine-rich protein 61 (CYR61) is one of the most differentially expressed genes between the groups and has been selected for a detailed molecular investigation. Direct sequencing of complete CYR61 gene revealed five polymorphisms with minor allele frequency >5% in the promoter region (rs 3753794, rs 3753793 and rs 2297140), intron 1 (rs 2297141) and intron 2 (IVS 2+50). Chi-square test and logistic regression were applied to test for association between CYR61 polymorphisms and the individual MS components in a cohort of 697 obese individuals. In men and women, rs 3753794 and rs 3753793 (r2 = 0.77) were associated plasma HDL-cholesterol levels (p = 0.016 and p = 0.008). Carriers of the A allele for rs 3753794 were more likely to have high plasma HDL-cholesterol levels (1.50-fold; p = 0.016), as compared with G/G homozygotes and the A/A homozygotes for rs 3753793 were more likely to exhibit low plasma HDL-cholesterol levels (1.56-fold; p = 0.008), as compared with C/C homozygotes. Furthermore, an association between IVS 2+50 polymorphism and HDL-cholesterol was found in women and in men analyzed separately (p = 0.002 and p = 0.038, respectively). These results suggest that CYR61 is a promising candidate gene for lipoprotein/lipid perturbations.