Introduction Hyperintense acute reperfusion marker (HARM) is an indicator of early disruption of the blood-brain-barrier. Our aim was to investigate the incidence of HARM in patients with a diffusion weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) mismatch and determine the association between this marker and hemorrhagic complications as well as clinical outcome. Patients and Methods We included patients from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial who underwent baseline perfusion weighted imaging (PWI). HARM was defined as a hyperintense signal in the cerebrospinal fluid space on FLAIR imaging at 24 h after baseline imaging. We compared baseline characteristics in patients with and without HARM and investigated the association between HARM and any hemorrhagic transformation (HT) and parenchymal hematoma (PH) in a multivariate logistic regression. We also explored HARM as an independent predictor of poor outcome, defined as a modified Rankin Scale of 3–6 at 90 days. Results HARM was present in 14 of 223 (6%) patients with a DWI-FLAIR mismatch and baseline characteristics were similar in patients with vs without HARM. HARM showed an independent relationship with any HT (OR 6.67; 95%CI 1.72–26.58) and any PH (OR 6.92; 95%CI 1.34–29.49). The rate of HARM was similar in patients with good and poor outcome (5%, p = 0.90). Conclusion In the WAKE-UP trial, the incidence of HARM was only 6% at 24 h. An association was present between HARM and hemorrhagic complications, but no relationship with functional outcome was observed.