Background Unloading the left ventricle and delaying reperfusion reduces infarct size in preclinical models of acute myocardial infarction. We hypothesized that a potential explanation for this effect is that left ventricular (LV) unloading before reperfusion increases collateral blood flow to ischemic myocardium. Methods and Results Acute myocardial infarction was induced by balloon occlusion of the left anterior descending artery for 120 minutes in adult swine, followed by reperfusion for 180 minutes. After 90 minutes of occlusion, animals were assigned to 30 minutes of continued occlusion (n=6) or to 30 minutes of support with either an Impella CP (n=4) or venoarterial extracorporeal membrane oxygenation (n=5) with persistent occlusion. The primary end point was measures of microcirculatory blood flow including the collateral flow index (CFI) during left anterior descending artery occlusion as (P -RA)/(P -RA), where P , P , and RA are aortic, coronary wedge, and right atrial pressure, respectively. Infarct size was quantified using triphenyltetrazolium chloride. Compared with continued occlusion, Impella, not venoarterial extracorporeal membrane oxygenation, reduced infarct size relative to the area at risk. Before reperfusion, Impella reduced LV stroke work by 25% and increased the CFI by 75%, but venoarterial extracorporeal membrane oxygenation did not. Among all groups, the change in CFI between 90 and 120 minutes correlated inversely with the change in LV stroke work ( =0.44, =0.01) and infarct size ( =0.41, =0.02). Conclusions We report for the first time that 30 minutes of LV unloading during coronary occlusion increases the CFI, which correlates inversely with LV stroke work and infarct size. Venoarterial extracorporeal membrane oxygenation failed to increase the CFI and did not reduce infarct size.