OBJECTIVE: To test the associations between the N363S polymorphism of the glucocorticoid receptor gene (NR3C1) and factors related to the metabolic syndrome in middle-aged men with and without juvenile-onset obesity. RESEARCH METHODS AND PROCEDURES: This study included two groups of middle-aged men, who were originally identified at 20 years of age at the draft boards. One group (n = 208; age, 48 +/- 6 years) was selected on the basis of juvenile-onset obesity (BMI > or = 31 kg/m(2)). The other group consisted of mainly nonobese men randomly sampled from the same population in parallel with the obese men (n = 299; age, 50 +/- 7 years). The subjects were genotyped for the N363S polymorphism by polymerase chain reaction-restriction fragment length polymorphism. Body composition was measured by DXA. Glucose metabolism was evaluated by an oral glucose tolerance test, and the Matsudas index was calculated as a proxy for insulin sensitivity. Serum triglycerides and total and high-density lipoprotein-cholesterol were measured in the fasting state. RESULTS: Among the men with juvenile-onset obesity, carriers (n = 17) of the 363S allele had a lower whole body fat percentage, after accounting for differences in BMI and higher Matsudas index, compared with the noncarriers. The difference in Matsudas index lost statistical significance after the difference in body fat was accounted for. In the randomly sampled men, these variables did not relate to genotype. No relationship between carriers and noncarriers was found in body fat distribution or serum lipids. DISCUSSION: This study suggests that, in men developing obesity early in life, the 363S allele is associated with less adiposity at a given BMI, leading to higher insulin sensitivity.