Abstract Body: Atherosclerosis is a persistent inflammatory disease characterized by the buildup of lipid-laden macrophages (foam cells) in arterial walls and has been linked to several cardiovascular ailments. Despite advances in understanding its pathogenesis, the underlying mechanisms of atherogenesis, particularly regarding chemokine influence, has yet to be investigated. Our laboratory has previously identified CXCL5, a chemokine known for its involvement in inflammatory responses, as a potential mediator of atherosclerosis. We found that patients with elevated CXCL5 levels were less likely to have experienced a previous heart attack or develop coronary artery disease, suggesting that CXCL5 may be atheroprotective. To further investigate the role of CXCL5 in atherosclerosis, we conducted a study using mice on an apolipoprotein E (apoE) knockout background, to promote the formation of plaque, with varying alleles (0, 1, or 2) of CXCL5. Mice were placed on a high-fat diet regimen starting at approximately 10 weeks of age and continued until 26 weeks of age. Aortas, echocardiograms, and blood plasma were obtained to assess the development of atherosclerosis and its impact on cardiac function and metabolic parameters. Our en face oil red o staining results showed that the aortas of mice lacking one (p=.0314) or both alleles (p=.0783) of CXCL5 exhibited elevated plaque formation compared to that of wild-type mice. Echocardiographic data revealed that left ventricular mass (corrected) was highest in CXCL5 knockout mice and increased significantly over time (p=.0170) in these animals. Additionally, a significant increase in heart rate (p=.0095) and glucose (p=.0274) levels was only observed in CXCL5 heterozygous mice over the 16-week period, while triglyceride levels increased in both CXCL5 heterozygous (p=.0010) and knockout (p=.0241) mice. Interestingly, high-density lipoprotein (HDL) levels, which is often considered as "good cholesterol," increased significantly only in wild-type (p=.0031) mice, where CXCL5 was present, over the 16-week period. These findings suggest that CXCL5 may play a protective role against atherosclerosis and its associated cardiac complications. In conclusion, our study provides novel insights into the complex interplay between inflammation, lipid metabolism, and cardiovascular disease, highlighting the potential therapeutic value of CXCL5 in the prevention and treatment of atherosclerosis.