Single-nucleotide polymorphisms (SNPs) in the SHBG gene are associated with type 2 diabetes mellitus. SHBG has also been proposed as a candidate gene for the polycystic ovary syndrome (PCOS).The study aims were 1) to determine whether any of four SHBG SNPs (rs1779941, rs6297, rs6259, and rs727428) are associated with PCOS and 2) to determine whether SNP genotype influences SHBG levels in PCOS women.Using the transmission disequilibrium test, evidence of associations between SHBG SNPs and PCOS were analyzed. Additionally, correlations between SHBG levels and SNP genotype, body mass index, non-SHBG-bound testosterone, and insulin resistance estimated by the homeostasis model were determined.The study was conducted at academic medical centers.A total of 430 families having a proband with PCOS were included in the family-based study. Associations between SNP genotypes, SHBG, and metabolic parameters were determined in 758 women with PCOS including probands from the family cohort.Primary outcome measures included transmission frequency of SNP alleles and correlation coefficients between SHBG and allele frequency/metabolic parameters.No evidence of association between SNPs of interest and PCOS was found. However, in multivariate analyses, SHBG levels varied significantly with rs1799941 and rs727428 genotype after controlling for body mass index, non-SHBG-bound testosterone, and homeostasis model for insulin resistance.Although SHBG SNPs associated with type 2 diabetes mellitus do not appear to be associated with PCOS status, rs1799941 and rs727428 genotypes are associated with SHBG levels independent of the effects of insulin resistance and obesity.