Simple SummaryThe relationship between vitamin D and calcium supplement use and breast cancer among women in the general population is not clear. Furthermore, whether such an association exists among women at high risk due to aBRCA1orBRCA2mutation has not been investigated. Thus, we evaluated the association between vitamin D and/or calcium supplement use and breast cancer in this high-risk population. In this case–control study, we identified 134 women diagnosed with breast cancer and 276 women without breast cancer. Women with aBRCAmutation who consumed vitamin D-containing supplements had 46% lower odds of having breast cancer compared to those who did not take any supplements. Increasing vitamin D and calcium supplement intake was inversely associated with the odds of having breast cancer. Higher vitamin D and/or calcium supplement intake may be associated with lower breast cancer risk in this high-risk population.AbstractThe role of vitamin D and calcium use in the development of breast cancer among women in the general population is not clear. Furthermore, whether vitamin D and calcium supplement use are associated with breast cancer in high-risk populations has not been evaluated. Thus, we evaluated the association between vitamin D and/or calcium supplement use and breast cancer among women with a pathogenic variant (mutation) inBRCA1orBRCA2.BRCAmutation carriers enrolled in a longitudinal study were invited to complete a supplemental questionnaire on lifetime supplement use. Cases included women with a prevalent diagnosis of invasive breast cancer, and controls had no history of breast cancer. Vitamin D and calcium use were categorized as never/ever use, and as tertiles of supplement intake (total average daily supplement use). Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CIs) of breast cancer. This study included 134 breast cancer cases and 276 controls. Women who used vitamin D-containing supplements had 46% lower odds of having breast cancer compared to those who never used supplements (OR 0.54; 95% CI 0.31, 0.91;p= 0.02). Increasing vitamin D and calcium supplement intake was inversely associated with the odds of having breast cancer (p-trend = 0.04). Findings were suggestively stronger among BRCA1 mutation carriers; however, analyses were limited by small strata. These findings suggest a potential inverse association between vitamin D and calcium supplementation andBRCAbreast cancer. Additional studies are warranted to confirm these findings and accurately inform clinical care guidelines.