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Recent epidemiological studies suggest that the risk factors of breast density and obesity together increase breast cancer risk in premenopausal women, and these women have a worsened prognosis following breast cancer diagnosis. Although the underlying causes of increased risk associated with dense breasts and obesity have individually been explored, little is known about how these underlying risk factors interact together to enhance breast cancer risk. To model breast density, we used heterozygous Col1a1tmjae mice, that have a mutation that limits collagen degradation, leading to increased mammary collagen deposition. Heterozygous (het) mice or wild type (wt) litter mates were fed either a control diet (CD) or a high fat diet (HFD) to induce obesity. We quantified F4/80-positive macrophages within mammary glands using immunohistochemistry. We observed significantly increased numbers of macrophages in mammary glands of CD/het, HFD/wt and HFD/het mice compared to CD/wt mice. We observed significantly enhanced picrosirius red stained collagen surrounding mammary ducts from CD/het, HFD/wt, and HFD/het mice compared to those from CD/wt mice. Notably, HFD/het mice had significantly more collagen surrounding ducts than in mammary glands from CD/het mice. These results may suggest that obesity enhances collagen deposition and macrophage-driven inflammation within dense breast tissue in the mammary glands of non-tumor-bearing mice. Citation Format: Abbey E. Williams, Abbey E. Williams, Erica Hoffman, Julia Warren, Suzanne Ponik, Lisa M. Arendt. Collagen density and obesity promote mammary gland inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2574.