Thirty-four subjects with symptomatic peripheral arterial disease (PAD) or critical limb ischmeia (CLI) who were experiencing claudication pain, chronic resting pain, numbness, and ischemic lower leg/foot ulceration were randomized into 2 treatment groups. Materials and Methods. Eighteen of these patients received treatment with high-pressure, intermittent pneumatic compression (HPIPC) 60 minutes twice daily for 16 weeks, and 16 subjects received standard care consisting of an exercise regimen of walking for 20 minutes twice daily for 16 weeks. The HPIPC device delivers bilateral pressures of 120 mm Hg. Cycle times provide sequential compression for 4 seconds (+/- 0.5 seconds) followed by a 16-second rest period (+/- 3.0 seconds), resulting in a 20-second cycle or 3 cycles per minute. The study was designed to measure patient-centered outcomes. The primary endpoint was peak walking time (PWT), defined as time to maximally tolerated claudication pain. Secondary endpoints included change in resting ankle brachial index, ulcer healing, relief of resting/wound pain, and quality of life (QoL) index. Age (73.7 years vs 72.7 years), baseline PWTs (1-6 minutes), and risk factors were similar in both treatment groups. Results. At 4 weeks, the percent change from baseline in PWT did not vary significantly between treatment groups (17.8% for HPIPC and 17% for standard care). After 8 weeks, the percent change in PWT for the HPIPC group was 41% compared to 32% for the group receiving standard care (P = 0.062). At the 16-week time point the percent change from baseline in PWT was significantly different between treatment arms (35.5% for the standard care group and 54.7% for the group receiving HPIPC [P = 0.043]). The mean reduction in wound surface area was 57% and 71% at 12 weeks and 16 weeks, respectively, for the HPIPC group, compared to 45% and 56% for the control group. The HPIPC group reported significantly greater pain relief at the 12-week (P = 0.044) and 16-week (P = 0.038) time points. Compared to the control group, the HPIPC group reported improvement in patient-centered outcomes such as physical function and bodily pain. These differences were statistically significant (P < 0.05) at the 16-week evaluation period. Conclusion. Therapy consisting of HPIPC for 2 hours daily for a period of 16 weeks significantly improved PWT, reduced resting pain, and improved healing rates, physical function, and bodily pain. There were no device-related complications, allowing for long-term use. This study further supports that HPIPC is safe and effective and should be considered for patients who are not candidates for endovascular or surgical procedures. Furthermore, HPIPC offers an excellent alternative for the palliative care of patients with PAD and CLI symptoms.