OBJECTIVE This study was conducted to (1) examine the effect of metabolic syndrome on intermittent claudication, physical function, health-related quality of life, and peripheral circulation in patients with peripheral arterial disease (PAD), and (2) determine whether peripheral vascular function was predictive of intermittent claudication and physical function in patients with metabolic syndrome. METHODS Patients limited by intermittent claudication and who had metabolic syndrome (n = 133) were compared with those without metabolic syndrome (n = 201). Patients were assessed on metabolic syndrome characteristics, PAD-specific measures consisting of ankle/brachial index and claudication distances, physical function measures, health-related quality of life, and calf blood flow and transcutaneous oxygen tension responses after 3 minutes of vascular occlusion. RESULTS Initial claudication distance (mean +/- SD) was 29% shorter (P = .018) in patients with metabolic syndrome than in the controls (128 +/- 121 meters vs 180 +/- 166 meters), and absolute claudication distance was 22% shorter (P = .025) in those with metabolic syndrome (319 +/- 195 meters vs 409 +/- 255 meters). Furthermore, patients with metabolic syndrome had lower peak oxygen uptake (P = .037), a shorter 6-minute walk distance (P = .027), lower values on six domains of health-related quality of life (P < .05), reduced calf hyperemia (P = .028), and greater calf ischemia (P < .001) after vascular occlusion. In the group with metabolic syndrome, calf ischemia was correlated with initial claudication distance (r = 0.30, P = .004), absolute claudication distance (r = 0.40, P < .001), and peak oxygen uptake (r = 0.52, P < .001). CONCLUSIONS Metabolic syndrome worsens intermittent claudication, physical function, health-related quality of life, and peripheral circulation in patients with PAD. Calf ischemia in those with metabolic syndrome was predictive of intermittent claudication and physical function. The additive burden of metabolic syndrome thus places patients who are limited by intermittent claudication at an even greater risk for living a functionally dependent lifestyle. Aggressive risk-factor modification designed to treat components of metabolic syndrome should be evaluated for efficacy in modifying physical and vascular function in patients with intermittent claudication.