We examined 483 Finnish breast cancer cases and 482 population controls to determine the potential effect of catechol-O-methyltransferase (COMT) genotype in individual susceptibility to breast cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression after adjustment for known or suspected risk factors for breast cancer. When studied separately by menopausal status, the COMT-L allele-containing genotypes were inversely associated with premenopausal breast cancer, especially with advanced stage of the disease (OR, 0.44; 95% CI, 0.22-0.87). Among postmenopausal women a similar decreased risk was seen for local carcinoma associated with the COMT-LL genotype (OR, 0.55; 95% CI, 0.31-0.98). The lowest breast cancer risk was seen in the postmenopausal women with the COMT-LL genotype and low body-mass index (<or=25.4 kg/m(2); OR, 0.33; 95% CI, 0.13-0.83). Significantly increased risk, on the other hand, was seen for postmenopausal women with the COMT-LL genotype and long-term (>30 months) use of estrogen (OR, 4.02; 95% CI, 1.13-14.3), or with the COMT-L allele-containing genotypes and early age (<or=12 years) at menarche (OR, 8.59; 95% CI, 1.85-39.8). Our study, therefore, suggests that the COMT genotype may define a portion of the individual breast cancer susceptibility that is associated with reproductive events and hormone exposure even if it does not seem to be a major overall risk factor for this malignancy.