Abstract: Background: Most studies on endocrine-disrupting chemicals and breast cancer have focused on single compounds and have produced inconclusive findings. Objectives: We assessed the combined estrogenic effects of mixtures of xenoestrogens in serum and their relationship to breast cancer risk. Methods: A total of 186 incident pretreatment breast cancer cases and 196 frequency-matched controls were randomly sampled from a large population-based multicase?control study in Spain. The total effective xenoestrogen burden attributable to organohalogenated xenoestrogens (TEXB-?) and endogenous hormones and more polar xenoestrogens (TEXB-?) was determined in serum samples using high-performance liquid chromatography and E-Screen bioassay. Odds ratios for breast cancer comparing tertiles of serum TEXB-? and TEXB-? were estimated using logistic models, and smooth risk trends were obtained using spline models. Results: Cases had higher geometric mean TEXB-? and TEXB-? levels (8.32 and 9.94 Eeq pM/mL, respectively) than controls (2.99 and 5.96 Eeq pM/mL, respectively). The fully adjusted odds ratios for breast cancer (95% confidence intervals) comparing the second and third tertiles of TEXB-? with the first tertile were 1.77 (0.76, 4.10) and 3.45 (1.50, 7.97), respectively, and those for TEXB-? were 2.35 (1.10, 5.03) and 4.01 (1.88, 8.56), respectively. A steady increase in risk was evident across all detected TEXB-? levels and a sigmoidal trend was observed for TEXB-?. Individual xenoestrogens showed weak and opposing associations with breast cancer risk. Conclusions: This is the first study to show a strong positive association between serum total xenoestrogen burden and breast cancer risk, highlighting the importance of evaluating xenoestrogen mixtures, rather than single compounds, when studying hormone-related cancers.

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