No / The expression and potential role of platelet membrane CD154 and sCD154 in atherosclerosis was investigated in patients with peripheral arterial disease. This prospective observational study measured the expression of platelet-bound CD154 and soluble CD154 (sCD154) in 39 patients with critical limb ischaemia (CLI, n = 15), stable intermittent claudication (SIC, n = 12) and age-matched controls (AMC, n = 12). Basal and agonist-stimulated CD154, P-selectin expression and fibrinogen binding was measured by whole blood flow cytometry, while sCD154 was measured in paired plasma samples by ELISA. Basal expression of CD154 on the platelet surface was enhanced in both groups of patients with peripheral arterial disease. However, the critical limb ischaemics showed the highest level of basal expression 0.7 ± 0.3 [median ± IQR] and was significantly increased compared to both stable intermittent claudicants and age-matched controls (P < 0.001). On agonist stimulation with either ADP or thrombin critical limb ischaemics demonstrated greater platelet reactivity and propensity to express CD154 compared to age-matched controls (P < 0.05). Confirmation of the cellular expression of CD154 results was obtained by measuring sCD154 concentrations in autologous plasma samples. Here plasma levels of sCD154 in critical limb ischaemics were significantly greater than both stable intermittent claudicants and age-matched controls (P < 0.005).