OBJECTIVES: This study aimed to determine whether remote ischemic conditioning (RIC) initiated prior to primary percutaneous coronary intervention (PPCI) could reduce myocardial infarct (MI) size in patients presenting with ST-segment elevation myocardial infarction. BACKGROUND: RIC, using transient limb ischemia and reperfusion, can protect the heart against acute ischemia-reperfusion injury. Whether RIC can reduce MI size, assessed by cardiac magnetic resonance (CMR), is unknown. METHODS: We randomly assigned 197 ST-segment elevation myocardial infarction patients with TIMI (Thrombolysis In Myocardial Infarction) flow grade 0 to receive RIC (four 5-min cycles of upper arm cuff inflation/deflation) or control (uninflated cuff placed on upper arm for 40 min) protocols prior to PPCI. The primary study endpoint was MI size, measured by CMR in 83 subjects on days 3 to 6 after admission. RESULTS: RIC reduced MI size by 27%, when compared with the MI size of control subjects (18.0 ± 10% [n = 40] vs. 24.5 ± 12.0% [n = 43]; p = 0.009). At 24 h, high-sensitivity troponin T was lower with RIC (2,296 ± 263 ng/l [n = 89] vs. 2,736 ± 325 ng/l [n = 84]; p = 0.037). RIC also reduced the extent of myocardial edema measured by T2-mapping CMR (28.5 ± 9.0% vs. 35.1 ± 10.0%; p = 0.003) and lowered mean T2 values (68.7 ± 5.8 ms vs. 73.1 ± 6.1 ms; p = 0.001), precluding the use of CMR edema imaging to correctly estimate the area at risk. Using CMR-independent coronary angiography jeopardy scores to estimate the area at risk, RIC, when compared with the control protocol, was found to significantly improve the myocardial salvage index (0.42 ± 0.29 vs. 0.28 ± 0.29; p = 0.03). CONCLUSIONS: This randomized study demonstrated that in ST-segment elevation myocardial infarction patients treated by PPCI, RIC, initiated prior to PPCI, reduced MI size, increased myocardial salvage, and reduced myocardial edema.