Leg thermotherapy (TT) application reduces blood pressure (BP) and increases both limb blood flow and circulating levels of anti-inflammatory mediators in healthy, young humans and animals. The purpose of the present study was to determine the impact of TT application using a water-circulating garment on leg and systemic hemodynamics and on the concentrations of circulating cytokines and vasoactive mediators in patients with symptomatic peripheral artery disease (PAD). Sixteen patients with PAD and intermittent claudication (age: 63±9 yrs) completed three experimental sessions in a randomized order: TT, control intervention and one exercise testing session. The garment was perfused with 48ºC water for 90 min in the TT session and with 33ºC water in the control intervention. A subset of 10 patients also underwent a protocol for the measurement of blood flow in the popliteal artery during 90 min of TT using phase-contrast MRI. Compared to the control intervention, TT promoted a significant reduction in systolic (~11 mmHg) and diastolic (~6 mmHg) BP (p<0.05) that persisted for nearly 2 hrs after the end of the treatment. The serum concentration of endothelin-1 (ET-1) was significantly lower 30 min after exposure to TT (Control: 2.3±0.1 vs. TT: 1.9±0.09 pg/mL, p=0.026). In addition, TT induced a marked increase in peak blood flow velocity (~68%), average velocity (~76%), and average blood flow (~102%) in the popliteal artery (p<0.01). These findings indicate that TT is a practical and effective strategy to reduce BP and circulating ET-1 concentration and enhance leg blood flow in patients with PAD.