High mammographic density (MD) is a strong risk factor for breast cancer. Chronic inflammation may be related to breast cancer risk through a mechanism involving the percent of breast area that is dense (percent MD). Longitudinal assessments, however, are lacking and thus were constructed to evaluate the relationship between chronic inflammation and percent MD. We evaluated whether elevated (>3 mg/L) high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammation, was associated with change in percent MD among 653 women aged 42-52 years at baseline in the Study of Women’s Health Across the Nation, a longitudinal study of midlife women. We used a mixed model to analyze data from an average of 4.7 mammograms per woman collected during an average follow-up of 4.9 years (SD = 1.47). Elevated hsCRP at baseline was associated with lower baseline percent MD and a significantly slower annual decline over time of percent MD in an adjusted model that did not include body mass index (BMI) (? = 0.88, 95 % CI 0.44, 1.31). This association was attenuated and nonsignificant when BMI was included in the model (? = 0.37, 95 % CI -0.09, 0.84). Elevated hsCRP levels over time (time-varying elevated hsCRP levels) were also associated with a significantly slower decline in percent MD (? = 0.62, 95 % CI 0.30, 0.94). This association was attenuated, but still significant after adjusting for baseline BMI (? = 0.40, 95 % CI 0.07, 0.73). These results suggest that inflammation may be related to slower reduction in percent MD.