Peripheral atherosclerosis manifests in both the extracranial carotid and lower extremity arteries and can lead to significant morbidity and mortality. However, atherosclerotic disease progression is often not homogenous and is accelerated by diabetes. We previously observed altered phospholipodomic profiles between minimally (MIN) and maximally (MAX) diseased peripheral arterial segments. Since Peroxisome Proliferator-Activated Receptor alpha ( pparα ) is a key regulator of lipid metabolism, we hypothesized that it may have variable content and signaling in MIN and MAX diseased arterial segments. To test our hypothesis, 12 patients who underwent carotid endarterectomy (CEA), and 19 patients who underwent major lower extremity amputation were recruited. MIN and MAX disease segments were obtained in real time from the operating room from CEA plaque and arterial segments from amputated lower extremities. mRNA was isolated from all specimens and relative content of pparα , Acyl-CoA Oxidase 1 ( acox1 ) , and Carnitine Palmitoyltransferase 1A ( cpt1a ) were evaluated. We observed significantly higher pparα expression in CEA segments in patients with diabetes (p < 0.01), as well as higher acox1 (p < 0.001) and cpt1a (p < 0.05) expression (A-C). Hemoglobin A1C had a significant correlation with ppara gene expression. There was no significant difference in gene expression between MAX and MIN diseased CEA plaque segments. Interestingly, we observed that in lower extremity arterial segments there was no difference in ppara , acox1 , and cpt1a in patients with and without diabetes, but downstream genes were significantly increased in MAX diseased arterial segments (D-F). This study demonstrates the variable expression pattern of pparα and its downstream genes in human peripheral arteries. Our findings suggest variable gene expression in different peripheral arterial beds, which may have an impact on mechanisms of disease progression and pharmacologic targeting.