Purpose: Women with PAD experience greater disease burden and complications, but the biological basis for these sex-specific outcomes remains unclear. This study investigates the sex-specific biology of atherosclerotic plaques by comparing plaque composition, inflammation, and oxidative stress in carotid and femoral arteries. Understanding these differences may inform more targeted diagnostic and therapeutic approaches for PAD. Methodology: Atherosclerotic plaques and plasma samples were collected from patients undergoing carotid (n=10) and femoral endarterectomies (n=10), with even sex-distribution. Gene expression analysis was performed for inflammation with Interleukin (IL)-1β, -18, -6 and Tissue Necrosis Factor-α (TNF-α) as well as oxidative stress via NADPH oxidase (NOX). Calcification was measured using calcium assays and Bone Morphogenetic Protein-2 (BMP-2) mRNA expression. Histological analyses were performed. Results: When stratified by sex, female plaques showed significantly lower collagen-I (p<0.05) and BMP-2 (p<0.05), suggesting greater plaque instability. Oxidative stress markers NOX-2 and NOX-4 were also reduced in females, suggesting reduced oxidative signalling in the plaque that may reflect impaired repair mechanisms that promotes stability. Furthermore, females with femoral artery disease exhibited significantly higher plasma IL-6 levels (p<0.05), indicating a more pronounced systemic inflammatory response. Male plaques were more inflamed, with elevated IL-1β and TNF-α expression (both p<0.05) Conclusion: Women with PAD exhibit more unstable plaque characteristics and heightened systemic inflammation. This may contribute to greater plaque instability, embolic risk, and the increased incidence of microvascular complications and limb amputation observed in female patients. These findings underscore the need for sex-specific diagnostic and therapeutic approaches to PAD tailored to the pathophysiology and clinical outcomes experienced by each sex.