Background: Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood. Methods: We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis. Results: Alcohol use was positively associated with PD (Ptrend ¼ 0.01), unassociated with DA (Ptrend ¼ 0.23), and inversely associated with NDA (Ptrend ¼ 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (Ptrend ¼ 0.0008), unassociated with DA (Ptrend ¼ 0.93), and positively associated with NDA (Ptrend<0.0001). These trends were stronger in normal and overweight women than in obese women. Conclusions: These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA. Impact: PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.