Objectives: Endothelial dysfunction assessed by brachial artery flow-mediated dilatation (FMD) has been associated with cardiovascular events. There have been relatively few studies examining FMD or other measures of endothelial function in patients with peripheral artery disease (PAD). The aim of this study was to examine determinants of FMD in a homogenous cohort of patients with PAD. Methods: We prospectively assessed patients presenting with life style-limiting intermittent claudication to establish the presence of cardiovascular risk factors, obesity and metabolic syndrome. Fasting serum was assayed for lipids, C-reactive protein, adiponectin, leptin, resistin and osteoprotegerin (OPG). FMD was measured by high-resolution ultrasound. Results: Serum concentrations of OPG were elevated in patients with obesity and metabolic syndrome. FMD was impaired in patients with obesity and metabolic syndrome and negatively correlated with serum concentrations of OPG. By multiple regression analysis, metabolic syndrome was independently associated with impaired FMD after adjustment for age, smoking, ischaemic heart disease, cerebrovascular disease and severity of PAD. Conclusions: Our findings suggest that metabolic syndrome is an important determinant of endothelial function in patients with PAD, and OPG may be a useful biomarker of this effect.