Lipid metabolism is regulated by a variety of physiological and pathophysiological pathways with as many as 95 genetic loci linked to lipid pathophysiology. In addition to the consumption of a “Western style” diet rich in saturated fats, defects in genes involved in the synthesis or processing of lipoproteins such as LDL can cause cholesterol to accumulate in the cells and extracellular matrix of the vasculature, leading to cardiovascular disease. A previous study has shown that average TC and LDL-C were significantly higher in individuals who sustained an Achilles Paclitaxel tendon injury compared to a control group, while high-density lipoprotein cholesterol concentration was significantly lower. Abboud and Kim reported similarly that rotator cuff tendinopathy patients demonstrate increased TC and LDL-C compared to controls. Surprisingly, mechanisms linking high fat diet and tendon pathology have not been directly examined. ApoE deficiency is a commonly used laboratory model of hypercholesterolemia. ApoE is required for normal catabolism and clearance of lipoprotein constituents, acting as a ligand for cell-surface LDL receptors; ApoE mice therefore experience a severe, progressive form of hypercholesterolemia, making them a common choice when studying the adverse influence of cholesterol on various body tissues. ApoE mice develop xanthomas – connective tissue deposits of lipid containing high levels of cholesterol and LDL and increased numbers of macrophages. The LDL component of xanthomas binds primarily to sulphated glycosaminoglycan to examine the impact of a high fat diet in mice on tendon oxLDL accumulation and tendon health, and to assess the effect of oxLDL on human tendon fibroblast function. In this study, we found that oxLDL accumulated in the tendons of mice consuming a high fat diet, and this accumulation was accompanied by an increased expression of Mmp2 and a reduction of structural and material properties. Human tendon cells exposed to oxLDL demonstrated a shift in phenotype, reducing their expression of collagen genes and increasing their expression of MMP2. We conclude that consumption of a high fat diet can impair the structure and function of tendon tissue and cellularity, and might predispose tenocytes to develop a pathological phenotype through excessive exposure to oxLDL. These observations could shed light on previously reported associations between hypercholesterolemia or increased LDL and tendon rupture, or tendinopathy, but further research is required to definitively identify a clinically validated risk factor for specific tendon injuries or conditions. MMP2 has also been shown to be upregulated in an animal model of tendinopathy and in tendinopathy patients. C57Bl/6 mice which consumed a high fat diet gained more weight than ApoE mice, and also demonstrated more peri-tendinous lipid deposition. We speculate that it may be physiological for fat to be stored in the loose connective tissue around tendons, an area sometimes referred to as mesotendon. Adipose tissue was indeed observed macroscopically, especially from the tendons of C57Bl/ 6 mice that consumed a high fat diet for 30 weeks.