PROJECT SUMMARY/ABSTRACT Objective. Our objective is to build on our preliminary work that a Non-IsChemic Exercise (NICE) program will be a better treatment for patients with peripheral artery disease (PAD) to improve ambulation, health-related quality of life (HRQoL), microvascular function, and systemic vascular biomarkers than a Standard painful exercise program. Specific Aims. We propose to test our central hypothesis that the NICE intervention performed without inducing leg ischemia and its’ damaging sequela will be a superior exercise paradigm to increase peak walking time and HRQoL more than the Standard ischemic and painful exercise paradigm via greater improvement in microvascular mechanisms. This clinically relevant hypothesis will be tested through the following aims: Aim 1 (Exercise Outcomes) To compare the changes in ambulation and HRQoL in PAD patients randomized to either the NICE slow walking program or to the Standard program of ischemic and painful exercise. Aim 2a (Vascular Outcomes) To compare the changes in local microvascular function of the lower extremities, inflammation and oxidative stress in patients following the NICE program, and following the Standard ischemic and painful program. Aim 2b (Exploratory Aim) To explore whether the changes in local microvascular function and systemic vascular biomarkers are associated with the changes in peak walking time following the NICE and Standard programs, and whether the association is stronger following the NICE program. Methods. This is a 3-month, patient-oriented, translational, comparative effectiveness randomized controlled trial. One-hundred patients will be randomized into either the NICE program (N=50) or the Standard exercise program (N=50). All patients will perform supervised treadmill walking for 3 months. Patients randomized to the NICE program will walk intermittently at a slow speed of approximately 1.4 mph for only 2-3 minute bouts that do not elicit claudication pain. Patients randomized to the Standard program will walk intermittently at a speed of approximately two mph to near maximal claudication pain. Clinical Significance. If successful, the NICE program which consists of slow-paced walking that does not elicit leg ischemia or pain will be a novel and innovative exercise program, and will be the exercise paradigm of choice to optimally improve peak walking time, HRQoL, local microvascular function, inflammation, and oxidative stress in PAD patients. These improvements could impact the clinical course of PAD by leading to healthier and more active lifestyles.