Objective: To investigate the relationship of the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala and silent exon 6 (His447His) polymorphisms with the clinical features of polycystic ovary syndrome (PCOS). Design: Patients with PCOS and control subjects were genotyped for Pro12Ala and His447His. Associations between genotype, diagnosis, and hormonal/metabolic parameters were assessed. Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham, Birmingham, Alabama. Control subjects were recruited from the surrounding community. Genotyping was performed at the Cedars-Sinai Medical Center in Los Angeles, California. Patient(s): Participants included 285 white women with PCOS and 187 controls. Intervention(s): None. Main Outcome Measure(s): The Pro12Ala and His447His genotypes, and hormonal and metabolic phenotypes. Result(s): The Pro12Ala and His447His genotypes did not influence risk of PCOS or its component phenotypes in patients with PCOS. In controls, Pro12Ala did not influence measures of insulin resistance or androgen production. However, carriers of the His447His T-allele had significantly decreased free and total T levels, and a significantly decreased homeostasis model assessment index of insulin resistance. Furthermore, haplotypes in controls bearing the His447His T-allele were also associated with decreased T. Conclusion(s): Peroxisome proliferator-activated receptor gamma does not appear to be an important modifier gene in PCOS. In controls, however, the His447His T-allele may be in linkage disequilibrium with a functional variant that influences insulin resistance and T production. © 2007 American Society for Reproductive Medicine.