Laboratory studies suggest a dual role for the transforming growth factor-beta (TGF-beta) signaling pathway in breast cancer. The normal antiproliferative activity of TGF-beta in early breast tumor development is replaced by a promoting effect in later stages. A T29C transition polymorphism in the TGFB1 gene has been associated with higher circulating TGF-beta1 levels, and inconsistently with breast cancer risk in three recent studies. We tested the association of this variant with invasive breast cancer in a case-control study of 1123 cases and 2314 controls nested in the Multiethnic Cohort (MEC) Study. This study is a large prospective study being conducted in Hawaii and Los Angeles that includes Japanese, white, African American, Latino, and Native Hawaiian women who were predominantly postmenopausal at baseline. After adjustment for breast cancer risk factors, the odds ratio (OR) and 95% confidence interval (95% CI) for the TGFB1 29 CC genotype was 0.95 (95% confidence interval: 0.76-1.18), compared to the TT genotype. Analyses stratified by race/ethnicity, stage, or age category did not reveal any association of this variant with breast cancer. Given the strong biological rationale and the scarce and divergent epidemiologic data to date, additional investigations of the relationship between breast cancer and genetic variants in the TGF-beta signaling pathway appear warranted.