HER-2 gene amplification and protein overexpression has been associated with increased risk of advanced-stage breast cancer and poor prognosis. Recently, a single missense point mutation (Ile(655)Val) in the transmembrane domain of the HER-2 gene was associated with a 40% increase in breast cancer risk among women 45 years of age and younger. In this analysis, we measured the association between the Ile(655)Val variant and postmenopausal breast cancer among women participating in the Hawaii and Los Angeles Multiethnic Cohort. Risk of localized breast cancer was significantly elevated among women with the HER-2 variant, but not among women with regional or metastatic disease. Women with at least one copy of the Valine variant were approximately one-half as likely to have high-stage as low-stage breast cancer (P =.02), and this effect was present across racial/ethnic groups.