Objective: To determine whether the frequency of the N363S variant of the glucocorticoid receptor (GRL) was increased in women with PCOS and adrenal androgen (AA) excess. Design: Prospective case-control study. Setting: University reproductive endocrinology laboratory and outpatient clinic. Patient(s): Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 92). Intervention(s): Blood and DNA sampling before hormonal therapy. Main Outcome Measure(s): PCOS patient and healthy control genotypes, with the N363S allele representing a variant of GRL. Result(s): Fifty-four PCOS patients with (DHEAS ≥ 3000 ng/mL) and 55 without (DHEAS ≤ 2,500 ng/mL) AA excess, respectively, were studied. Six of 109 (5.5%) patients studied were found to be heterozygous carriers of the A→G base pair substitution at cDNA position 1220, resulting in the missense mutation N363S. Of these six, four had excessive AA secretion (i.e., excess DHEAS levels). There was no significant difference in the allele frequency of the GRL variant between PCOS patients with and without AA excess and controls (3.7% [95% confidence interval: 1.0%-5.7%], 1.8% [0.2%-6.0%], and 3.3% [2.3%-6.0%]). None of the subjects were found to be homozygous for the N363S allele. Conclusion(s): The N363S variant of GRL was an uncommon occurrence in our population of healthy women and PCOS patients and did not appear to play a major role in the genetic predisposition to PCOS or to AA excess in PCOS. Copyright (C) 2000 American Society for Reproductive Medicine.