Remote ischemic preconditioning (RIPC) is a clinical procedure aimed at inducing myocardial protection by causing brief ischemia-reperfusion episodes in an organ remote from the heart. We aim to assess whether RIPC provides myocardial protection in patients undergoing non-cardiac surgery. This study, called remote ischemic PReconditioning In Non-Cardiac surgEry (PRINCE), is a double-blind, multinational randomized clinical trial (1:1 allocation ratio) which plans to enroll 1100 patients. The intervention arm will receive RIPC at the beginning of surgery by inflating a blood pressure cuff around a limb for three cycles of ten minutes (inflated cuff for five minutes followed by deflated cuff for five minutes). In the control group, a blood pressure cuff will be put on a limb, and a sham inflation will be performed. Given a potential interaction of propofol with RIPC, induction and maintenance of anesthesia will be performed without propofol. The primary endpoint of the study is to document a significant reduction in postoperative cardiac troponin values among patients receiving RIPC. Secondary endpoints will be cardiac ischemic events at 30 days and 1 year, mortality at 30 days and 1 year, neurologic events at 30 days and 1 year, acute kidney injury at 7 days, need for intensive care unit admission and length of hospital stay. The trial will provide evidence for the effects of RIPC on cardioprotection and other relevant outcomes in high-cardiac risk patients undergoing non-cardiac surgery. Clinical Trial Registration: NCT02427867.