Objective: To study the role of genetic variation in the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) gene in polycystic ovary syndrome (PCOS). Design: Women with and without PCOS were genotyped for seven single-nucleotide polymorphisms (SNPs) in HMGCR. The SNPs and haplotypes were determined and tested for association with PCOS and its component traits. Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. Patient(s): A total of 287 white PCOS women and 187 control subjects were studied. Intervention(s): Phenotypic and genotypic assessment. Main Outcome Measure(s): HMGCR genotype, PCOS diagnosis, androgen levels, metabolic traits. Result(s): No association with PCOS was observed. SNP rs4629571 was associated with increased insulin resistance. Haplotype 3 was associated with increased insulin resistance. Haplotype 5 was associated with higher SHBG and lower free T. Conclusion(s): Variation in the HMGCR gene may influence component features of PCOS, including insulin resistance, SHBG, and free T. HMGCR may thus act as a modifier gene in PCOS. © 2010 American Society for Reproductive Medicine.