To describe the influence of the TTTA aromatase polymorphism (TTTAn) on the relation between obesity and plasma estradiol (E 2 ) in obese men.A 2-year cohort study.Clinical research center.Severely obese men (31 who had had gastric bypass surgery and 118 controls).Men were genotyped for the TTTAn CYP19A1 polymorphism. Anthropomorphic measures, plasma E 2 , and other hormonal levels were determined at baseline and 2-year follow-up.Relationships between weight and changes in weight and plasma E 2 were examined in relation to the TTTAn polymorphism.The mean age was 46.5 ± 10.82 years, and mean body mass index was 47.1 ± 8.46 kg/m 2 . The most common repeats were 7 and 11. TTTAn number did not correlate with plasma E 2 in the univariate analysis. When patients were stratified per weight group, the correlation between plasma E 2 and weight was seen only among men with a higher TTTA repeat at baseline and 2 years. Similarly, only men with higher TTTA exhibited reduced E 2 levels after weight loss.A higher TTTA repeat is associated with a strengthened relationship between obesity and E 2 . The well-established effect of increased weight on plasma E 2 appears to be absent in men with low TTTA numbers.