Background-Peripheral artery disease is a major socioeconomic challenge in the diabetes mellitus community and non-surgical treatment options are limited. As remote ischemic conditioning (RIC) improves vascular function and attenuates ischemia-induced tissue damage, we investigated the efficacy of RIC on vascular and neuronal function in type 2 diabetes mellitus patients with peripheral artery disease. Methods and Results-We enrolled 36 type 2 diabetes mellitus patients with moderately reduced toe pressure (40-70 mm Hg) in a randomized sham-controlled double-masked trial. Patients were allocated to 12 weeks once daily upper arm cuff-based treatment of either RIC treatment (4 cycles of 5-minute ischemia followed by 5-minute reperfusion) or similar sham-device treatment. Primary outcome was transcutaneous tissue oxygen tension of the instep of the feet. Secondary outcomes were aortic pulse wave velocity, toe pressure and toe-brachial index. Tertiary outcomes were markers of peripheral and autonomic nerve function. We enrolled 36 patients (83% men). Patients had a mean (SD) age of 70.7 years (6.8), diabetes mellitus duration of 18.4 years (8.3), HbA1c (gycated hemoglobin) of 59.7 mmol/mol (11.2). Eighty percent had peripheral symmetrical neuropathy. The mean difference in change of transcutaneous tissue oxygen tension from baseline between the RIC and sham-treated groups was -0.03 mm Hg ([95% CI -0.1; 0.04], P=0.438). RIC did not elicit any change in additional outcomes. Three patients experienced transient skin petechiae in the treated arm. Conclusions-Long-term repeated remote ischemic conditioning treatment have no effect on tissue oxygenation, vascular or neuronal function in patients with type 2 diabetes mellitus and moderate peripheral artery disease.