PURPOSE: To determine whether calf muscle oxygen saturation (StO2) and vascular biomarkers of inflammation and oxidative stress were associated with an exercise pressor response during treadmill walking in patients with symptomatic peripheral artery disease (PAD). METHODS: A total of 179 patients were characterized on demographic variables, comorbid conditions, cardiovascular risk factors, ankle/brachial index, peak walking time (PWT), claudication onset time (COT), and calf muscle oxygen saturation (StO2) during a graded maximal treadmill test. The exercise pressor response was measured as the change in blood pressure from rest to the end of the first 2-minute treadmill exercise work stage (2 mph, 0% grade). Patients were further characterized on endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells, and on circulating inflammatory and vascular biomarkers. RESULTS: During the maximal treadmill test, patients experienced COT at 197±164 seconds (mean±SD) and PWT at 395±254 seconds. There was a wide range in the change in systolic blood pressure (-46 to 50 mm Hg) and in diastolic blood pressure (-23 to 38 mm Hg), with mean increases of 4.3 mm Hg and 1.4 mm Hg, respectively. In multiple regression analyses, significant predictors of systolic blood pressure included glucose (p<0.001) and insulin (p=0.039). The significant predictors of diastolic blood pressure included cultured endothelial cell apoptosis (p=0.019), the percentage drop in exercise calf muscle StO2 (p=0.023), high sensitivity C-reactive protein (p=0.032), and glucose (p=0.033). CONCLUSION: Higher levels in pro-inflammatory vascular biomarkers, impaired calf muscle StO2 during exercise, and elevated blood glucose were independently associated with greater exercise pressor response in patients with symptomatic PAD. The clinical implication is that exercise and nutritional interventions designed to improve inflammation, microcirculation, and glucose metabolism may ameliorate the exercise pressor response in patients with symptomatic PAD.