BACKGROUND: The value of distal protection devices during rescue PCI has not been studied. METHODS: The population enrolled in a prospective, randomized multicenter trial of distal microcirculatory protection in ST-elevation MI, was stratified for those undergoing rescue (n = 93) or primary (n = 408) PCI; we performed the prespecified comparisons of distal protection in rescue and primary PCI. RESULTS: Compared to primary PCI, rescue patients had higher baseline rates of TIMI-3 flow, but lower rates of post PCI TIMI-3 flow. However, no differences in the primary endpoints of complete ST-segment resolution (STR) at 30 minutes or infarct size, or 6 month mortality were present. In rescue PCI patients, randomization to distal protection did not significantly affect infarct size, STR, mortality or other clinical events. CONCLUSION: Despite reduced rates of post-procedural TIMI-3 flow, patients undergoing rescue PCI compared to primary PCI have similar myocardial perfusion, infarct size and clinical outcomes. Distal protection did not offer any detectable benefit in this patient population.