Reactive oxygen species are important in the pathogenesis of many diseases, including breast cancer. Several population-based case-control studies have shown that various biomarkers of oxidative stress are associated with an increase in breast cancer risk. We selected sisters discordant for breast cancer (n=645) from the New York site of the Breast Cancer Family Registry to explore factors that contribute to variation in plasma protein carbonyls, and to determine whether this biomarker is associated with an increase in breast cancer risk among those with a family history. Late age at menarche, hormone replacement therapy use, and Hispanic race were significantly associated with lower plasma protein carbonyl levels in unaffected sisters. Plasma protein carbonyls were associated with an increase in breast cancer risk [Q2 odds ratio (OR), 1.4; 95% confidence interval (CI), 0.8-2.7; Q3 OR, 2.4; 95% CI, 1.1-4.9; Q4 OR, 1.9; 95% CI, 0.8-4.2], although not in a dose-dependent manner. These data suggest that oxidative damage is a risk factor for breast cancer in high-risk women.