The process of atherosclerosis receives major contributions from inflammatory mechanisms. The white blood cell (WBC) count (even in the normal range) is a major predictor for cardiovascular events. WBCs contribute to atherosclerosis through both physical and chemical means. Increased WBC aggregation and levels of cell adhesion molecules are found in claudication and are highest in those predestined to progress to critical limb ischaemia. The products released from WBCs also contribute to the atherosclerotic process. Indirect markers of free radical activity/oxidative stress are increased in intermittent claudication, and are again highest in those predestined to develop critical limb ischaemia. The abnormalities detected are linked to poor endothelial cell function that further promotes vascular disease. The physical obstructive effects of WBCs, combined with the oxidative stress generated by these WBCs and other mechanisms such as reperfusion, have a potential deleterious effect in patients with peripheral arterial disease. We must focus future studies and evolving therapies to this area.