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Background: Certain metals are known or suspected carcinogens and have been found in breast tissue samples. Toenails are a stable matrix that reflect exposure 6-12 months before collection and measurements correlate well over time. We prospectively examined a large panel of toenail metals in relation to breast cancer risk and were the first to consider whether multiple metal biomarkers jointly influence risk. Methods: The Sister Study is prospective cohort of 50,884 women who enrolled between 2003-2009 with follow-up for breast cancer through September 2016. We measured 15 metals in toenails collected at enrollment using a case-cohort design of 1,495 cases and a randomly-selected sub-cohort of 1,605 women. For individual metals, multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression with robust variance. We examined associations overall and stratified by race, estrogen receptor (ER), and menopausal status. Quantile g-computation was used to examine joint associations between multiple metals and breast cancer risk. Results: In individual metal models, arsenic was associated with a non-linear increase in breast cancer risk (2^nd vs. 1^st tertile, HR=1.22; 95% CI: 1.01-1.49). This association was stronger for ER+ breast cancer (HR=1.31; 95% CI: 1.06-1.62). In non-Hispanic Blacks, zinc was associated with an elevated risk (3^rd vs. 1^st tertile, HR=1.40; 95% CI: 0.97-2.02). Molybdenum was inversely associated with breast cancer overall (3^rd vs. 1^st tertile, HR=0.83; 95% CI: 0.68-1.00) and particularly for ER- breast cancer (3^rd vs. 1^st tertile, HR=0.57; 95% CI: 0.37-0.87). A simultaneous increase in multiple metals was not associated with breast cancer risk. Conclusions: In this prospective study considering multiple toenail metals in relation to breast cancer, we found that individual metals and metal mixtures were not consistently associated with a higher risk. However, a few metals appeared to be related to breast cancer risk in certain subgroups.