ABSTRACT BACKGROUND Reperfusion of penumbral tissue is a promising strategy for treatment of acute cerebral ischemia more than 3 hours from symptom onset. However, there has been only sparse direct evidence that reperfusion after 3 hours prevents infarct growth. METHODS We analyzed clinical and serial magnetic resonance imaging (MRI) data on patients who received endovascular recanalization therapy 3‐12 hours after last known well time. Multimodal MRIs were acquired pretreatment, early (1‐20 hours), and late (2‐7 days) after treatment. Degree of recanalization was assessed on end of procedure catheter angiogram, degree of reperfusion on early posttreatment perfusion MRI, and infarct growth by analysis of diffusion lesion volumes on pretreatment and late MRIs. RESULTS Twenty‐seven (12 men, 15 women) underwent endovascular recanalization procedures at 6.0 ± 2.1 hours (range, 3.0‐11.5 hours) after last known well time. Immediate posttreatment perfusion lesion (Tmax ≥4 seconds) volume correlated strongly with infarct growth (r= .951, P < .001), exceeding the correlations of vessel recanalization score (r=−.198, P= .446) and pretreatment diffusion‐perfusion mismatch volume (r= .518, P= .033). Without reperfusion, enlargement of DWI lesion volume was observed in all patients, and extent of enlargement depended on volume of immediate posttreatment perfusion defects. CONCLUSION Our data indicate that posttreatment reperfusion is the major determinant of threatened tissue outcome, and suggest reperfusion even after 3 hours of symptom onset can alter tissue fate over a wide range of mismatch volumes.