Obesity has reached epidemic proportions worldwide contributing to the pathophysiology of many diseases including type 2 diabetes, cardiovascular disease, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). As such, there is an urgent need for new therapeutics to halt the exponential rise in individuals presenting with these conditions. Increased lipotoxicity and ceramide accumulation has been attributed to be a major player in the progression of obesity-associated diseases. Therefore, targeting ceramide accumulation is an attractive target for manipulation. Fenretinide (FEN) is a synthetic retinoid that blocks ceramide accumulation in adipose and liver tissue in both high-fat diet-fed mice and genetically-obese diabetic mice and prevents obesity and insulin resistance. However, the potential beneficial effects of FEN in either NAFLD or atherosclerosis is unknown. We sought to answer these questions using the LDLR-/- mouse model of atherosclerosis. All animal procedures were performed under a project license approved by the U.K. Home Office under the Animals (Scientific Procedures) Act 1986. Mice were fed either control (n=14) or high cholesterol/high fat diet (HFD, n=18) for 14 weeks to induce atherogenesis and steatosis with or without 0.04% FEN (HFD-FEN, n=18). Data are expressed as mean ±S.E.M, and analysed by either one- or two-way ANOVA, followed by Bonferroni multiple comparison tests. FEN treatment prevented weight gain in LDLR-/- mice, specifically due to fat mass accumulation, and exhibited increased sensitivity to insulin when compared to mice fed HFD alone (p<0.001 and p<0.01 respectively, n=10 per group). Hepatic genetic analysis revealed that HFD increased expression of the inflammatory cytokines TGF1β (3-fold, p<0.05) and TNFα (10-fold, p<0.05), and the fibrosis genes collagen (3-fold; Col1a1, Col4a1, p<0.01 and p<0.05 respectively) and matrix metallopeptidase protein 9 (10-fold MMP9, p<0.001). These were restored to control levels following FEN exposure. Fibrotic gene changes were reciprocated at the protein level as HFD-FEN fed mice had two-fold less MMP2 (p<0.05) than those on HFD alone. Finally, increased liver triglycerides are a hallmark of NAFLD. When compared to control mice, HFD feeding resulted in significantly increased liver triglycerides (14.24±1.47 versus 35.28±6.39 µg/mg protein, p<0.01) which was attenuated following the addition of FEN to the diet (13.82±0.97 µg/mg protein). Taken together these data indicate, in addition to weight loss and restoring insulin sensitivity, FEN has beneficial effects on liver steatosis. Hence, this compound could also be used to curb NAFLD progression. Further analyses of tissues, including aortic atherosclerotic plaque formation, may reveal further beneficial phenotypes of FEN treatment in LDLR-/- mice.