Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of estrogen catechols. In a case-control study, we evaluated the association of the low-activity allele (COMT^Met) with breast cancer risk. Compared to women with COMT^Val/Val, COMT^Met/Met was associated with an increased risk among premenopausal women [odds ratio (OR), 2.1; confidence interval (CI), 1.4–4.3] but was inversely associated with postmenopausal risk (OR, 0.4; CI, 0.2–0.7). The association of risk with at least one low-activity COMT^Met allele was strongest among the heaviest premenopausal women (OR, 5.7; CI, 1.1–30.1) and among the leanest postmenopausal women (OR, 0.3; CI, 0.1–0.7), suggesting that COMT, mediated by body mass index, may be playing differential roles in human breast carcinogenesis, dependent upon menopausal status.