Background: Mammographic density is an important risk factor for breast cancer but the etiology of density is not well understood. Studies suggest that inflammation may play a role in density. We evaluated the association between serum inflammatory markers and breast density in women at increased risk for breast cancer. Methods: Women previously enrolled in the University of Vermont IRB-approved High-Risk database were eligible for inclusion if they had a baseline serum sample and a mammogram available within 120 days of each other (N = 174). A subset of eligible women also had a paired serum sample and mammogram at 4 years from study entry (N = 38). Blood samples were analyzed for C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1b (IL-1b) and tumor necrosis factor-α (TNF-α). Breast density was calculated using 2 methods; the semi-automated Cumulus method and fully automated University of Pennsylvania (UPenn) method. Results: Mean age of the cohort was 46.2 (range 24-71 years) and 63.8% were premenopausal. Mean baseline density was 35.8% and 31.8% using the Cumulus and UPenn method respectively. Mean baseline values were 20,005 ng/ml for CRP, 10.6 pg/ml for TNF-α, 0.78 pg/ml for IL-1b and 0.84 pg/ml for IL-6. Body mass index correlated with CRP (spearman correlation coefficient [r] = 0.58; p< 0.0001), IL-6 (r = 0.17; p= 0.003) and TNF-α (r = 0.19; p= 0.02).Linear regression adjusted by age and BMI found that baseline IL-6 had significant association with breast density calculated by either density methods (Cumulus: β coefficient 1.62, p= 0.04; UPenn: β coefficient 1.95, p= 0.01). No other biomarker had a statistically significant relationship with density. There was no significant correlation between change in inflammatory marker levels and change in density at 4 years. Conclusions: Mammographic breast density was found to be elevated among women with higher serum IL-6 levels, a finding that supports prior data suggesting a relationship between inflammation and density. This study strengthens the evidence for consideration of anti-inflammatory agents as chemoprevention for breast cancer. Further research is needed to elucidate the mechanism by which IL-6 is associated with breast density.