Mammographic density is one of the strongest predictors of breast cancer risk. Recently, it has been suggested that reactive oxygen species may influence breast cancer risk through its influence on mammographic density. In the current study, we addressed this hypothesis and also assessed if the association between carotenoids and breast cancer risk varies by mammographic density. We conducted a nested case-control study consisting of 604 breast cancer cases and 626 controls with prospectively measured circulating carotenoid levels and mammographic density in the Nurses' Health Study. Circulating levels of alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, and lutein/zeaxanthin were measured. We used a computer-assisted thresholding method to measure percent mammographic density. We found no evidence that circulating carotenoids are inversely associated with mammographic density. However, mammographic density significantly modified the association between total circulating carotenoids and breast cancer (P heterogeneity = 0.008). Overall, circulating total carotenoids were inversely associated with breast cancer risk (P trend = 0.01). Among women in the highest tertile of mammographic density, total carotenoids were associated with a 50% reduction in breast cancer risk (odds ratio, 0.5; 95% confidence interval, 0.3-0.8). In contrast, there was no inverse association between carotenoids and breast cancer risk among women with low mammographic density. Similarly, among women in the highest tertile of mammographic density, high levels of circulating alpha-carotene, beta-cryptoxanthin, lycopene, and lutein/zeaxanthin were associated with a significant 40% to 50% reduction in breast cancer risk (P trend < 0.05). Our results suggest that plasma levels of carotenoids may play a role in reducing breast cancer risk, particularly among women with high mammographic density.