Abstract Mammographic density is an important risk factor for breast cancer and is known to differ in women by characteristics such as age and race/ethnicity. Women who experience longitudinal decreases in breast density have a reduced risk of breast cancer; however, besides age, which correlates with decreases in breast density, it is unclear what other factors contribute to changes in breast density over time. Understanding factors associated with density changes may enable a better understanding of breast cancer risk and potential strategies for prevention. This study investigated factors associated with changes in mammographic density in a cohort of 3,392 postmenopausal women (mean age=61.3±8.8 years) with no history of breast cancer who had at least two mammograms spaced at least three months apart at a University of California, Irvine Health breast imaging facility between 2011-2017. Self-reported information on demographics, breast and reproductive history, and lifestyle factors, including body mass index (BMI), alcohol intake, smoking, and physical activity, was collected by an electronic intake form, and Breast Imaging Reporting and Database System (BI-RADS) mammographic density scores were obtained from electronic medical records. 7.9% of women exhibited a longitudinal decrease in mammographic density, 6.7% exhibited an increase, and 85.4% exhibited no change. Longitudinal changes in mammographic density were statistically significantly correlated with age, race/ethnicity, and age at menopause by univariate analysis using the Fisher’s exact test. Multivariate conditional logistic regression using baseline mammographic density as strata was performed to identify factors associated with a longitudinal increase or decrease in mammographic density. Variables were selected if they were nominally significant (p < 0.10) in the initial univariate analyses of women who exhibited a longitudinal change in mammographic density (race/ethnicity, age at baseline, menopause age) or were otherwise selected a priori based on previous literature showing an association with mammographic density (alcohol, physical activity, BMI). Asian women were more likely to exhibit a longitudinal increase in mammographic density (OR=1.78, 95% CI=1.02-3.09, p=0.04) and less likely to exhibit a decrease (OR = 0.58, 95% CI = 0.40-0.83, p=0.003) compared to white women. On the other hand, overweight and obese women were less likely to exhibit an increase compared to normal weight women (OR = 0.52, 95% CI = 0.31-0.87, p=0.01; OR = 0.41, 95% CI = 0.23-0.75, p=0.004, respectively). Other lifestyle factors (alcohol intake, smoking, and physical activity) were not associated with longitudinal changes in mammographic density. The potential interactions of Asian race and BMI with longitudinal breast density changes in influencing breast cancer risk should be further studied. Citation Format: Roza L. Kirmizi, Christie J. Lee, Hannah Lui Park, Argyrios Ziogas, Andrea Alvarez, Rachel M. Lucia, Deborah Goodman, Kathryn M. Larsen, Richard Kelly, Hoda Anton-Culver, Stephen A. Feig. Factors associated with longitudinal changes in mammographic density in a multiethnic breast screening cohort of postmenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5892.