Background: Observational studies have reported an inverse association between vitamin D status and breast cancer risk. We examined whether high-dose vitamin D supplementation among high-risk premenopausal women reduces mammographic density (MD), a strong predictor of breast cancer risk. Methods: We conducted a multicenter randomized double-blind placebo-controlled trial among premenopausal women at high risk for breast cancer [5-year Gail risk score ≥1.67%, lobular carcinoma in situ, prior stage 0-II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)] and with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤32 ng/mL. Subjects were randomized 1:1 to 1 year of vitamin D3 20,000 IU/week or matching placebo. All received standard-dose vitamin D 600 IU/day. The primary endpoint was change in MD from baseline to 1 year as assessed by the Cumulus technique. Secondary endpoints were serial blood biomarkers [25(OH)D, 1,25(OH)D, parathyroid hormone, insulin-like growth factor (IGF)-1, IGF binding protein-3] and MD change at 2 years. Results: Among 208 subjects registered from December 2011 to April 2014, median age was 44.6 years (range, 21-50); 84% were white; 33% had a baseline serum 25(OH)D < 20 ng/mL; 78% had a high baseline MD. At 1 year, we observed a significant mean change in serum 25(OH)D in the active vs. placebo group (+18.9 vs. +2.8 ng/mL, p < .01), but non-significant change for IGF-1 (-9.8 vs. -1.8 ng/mL, p = 0.28). Mean absolute change in MD at 1 year and 2 years after randomization was -0.3% and -1.2%, respectively, in the active arm and +1.5% and +1.6%, respectively, for the placebo arm (p > 0.05). At 1 year, MD correlated with serum IGF-1 and IGF-1/IGFBP-3 (p < .01). High-dose vitamin D3 was well-tolerated. Conclusions: Changes in MD at 1-2 years were small and did not significantly differ between high-dose and standard-dose vitamin D. Longer exposure may be required to detect a difference. The relationship between vitamin D, IGF-1, and MD are hypothesis-generating. Understanding the relationship between vitamin D and biomarkers of breast cancer risk may inform future clinical trials. Clinical trial information: NCT01097278