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Importance Although breast density is an established risk factor for breast cancer, longitudinal changes in breast density have not been extensively studied to determine whether this factor is associated with breast cancer risk. Objective To prospectively evaluate the association between change in mammographic density in each breast over time and risk of subsequent breast cancer. Design, Setting, and Participants This nested case-control cohort study was sampled from the Joanne Knight Breast Health Cohort of 10 481 women free from cancer at entry and observed from November 3, 2008, to October 31, 2020, with routine screening mammograms every 1 to 2 years, providing a measure of breast density. Breast cancer screening was provided for a diverse population of women in the St Louis region. A total of 289 case patients with pathology-confirmed breast cancer were identified, and approximately 2 control participants were sampled for each case according to age at entry and year of enrollment, yielding 658 controls with a total number of 8710 craniocaudal-view mammograms for analysis. Exposures Exposures included screening mammograms with volumetric percentage of density, change in volumetric breast density over time, and breast biopsy pathology-confirmed cancer. Breast cancer risk factors were collected via questionnaire at enrollment. Main Outcomes and Measures Longitudinal changes over time in each woman's volumetric breast density by case and control status. Results The mean (SD) age of the 947 participants was 56.67 (8.71) years at entry; 141 were Black (14.9%), 763 were White (80.6%), 20 were of other race or ethnicity (2.1%), and 23 did not report this information (2.4%). The mean (SD) interval was 2.0 (1.5) years from last mammogram to date of subsequent breast cancer diagnosis (10th percentile, 1.0 year; 90th percentile, 3.9 years). Breast density decreased over time in both cases and controls. However, there was a significantly slower decrease in rate of decline in density in the breast that developed breast cancer compared with the decline in controls (estimate = 0.027; 95% CI, 0.001-0.053; P = .04). Conclusions and Relevance This study found that the rate of change in breast density was associated with the risk of subsequent breast cancer. Incorporation of longitudinal changes into existing models could optimize risk stratification and guide more personalized risk management.