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BACKGROUND: Acute limb ischemia (ALI) requires urgent revascularization but this can cause ischemia/reperfusion injury. Remote ischemic preconditioning (RIPC) has shown benefit in reducing infarct size and improving endothelial function in acute myocardial ischemia. We hypothesized that RIPC may mitigate adverse outcomes in ALI following revascularization. METHODS: In a triple-blinded, randomized controlled trial, 28 ALI patients (Rutherford Classes 1-2b) scheduled for surgical revascularization were assigned to RIPC or control groups. The primary outcome was changes in kidney function; secondary outcomes included oxidative stress, mitochondrial function in peripheral blood mononuclear cells (PBMCs), and clinical outcomes. RESULTS: Fourteen patients were in each group, and baseline characteristics were similar. Changes in kidney function (creatinine clearance, neutrophil gelatinase-associated lipocalin) did not differ between groups. No significant differences were found in hospital stay, local complications (compartment syndrome, muscle necrosis), or systemic complications (heart failure, pulmonary edema, 30-day amputation/mortality). At the cellular level, RIPC reduced mitochondrial oxidative stress in PBMCs at 24 hours postrevascularization (P < 0.05) but had no effect on overall cellular oxidative stress. Mitochondrial function was decreased 24 hours postoperation in both groups; RIPC did not modify this effect. CONCLUSION: RIPC did not significantly affect renal function, clinical outcomes, or cellular changes in ALI patients, though it transiently reduced mitochondrial oxidative stress. These results suggest limited clinical benefit of RIPC in this setting. Larger studies are needed to further explore the protective mechanisms of RIPC in ALI.