Introduction: High-Frequency Irreversible Electroporation (H-FIRE) is a novel ablation technique that utilizes high energy (1-4 kV), ultrashort duration (0.5-5) bursts of bipolar pulses (energized for 50 to 200 ) to destabilize the cell membranes of target tissue and induce nonthermal tissue ablation that preserves critical vasculature, myelin sheaths, and connective tissue 1–3. Our focus in this study is towards the development of H-FIRE to eradicate glioblastoma multiforme (GBM), a brain tumor demonstrating a patient median survival of only 15 months. GBM resistance to standard treatment (chemotherapy, radiation, and resection) is partly due to protection from the blood-brain-barrier (BBB) and infiltration of glioma cells up to 2 cm beyond the solid tumor margin. Preclinical studies have shown H-FIRE induces temporary BBB disruption centimeters beyond the ablation volume, allowing for enhanced delivery of chemotherapeutics to the brain 4,5. The creation of numerical pre-treatment planning models allows for accurate prediction of both the tumor ablation and BBB disruption volumes in response to H-FIRE. In this study, we utilize a realistic human head model to predict zones of ablation and BBB disruption in response to various H-FIRE treatment parameters (i.e. number of bursts, voltage, etc.) to treat a simulated brain tumor.Methods: The realistic human head model was segmented using 3D Slicer, an open source platform for medical image informatics. The model was then meshed using 3-matic software (Materialise, Leuven, Belgium) and finally exported into COMSOL Multiphysics v5.3 (COMSOL Inc., Stockholm Sweden) for finite element analysis. Electrical tissue properties for porcine brain tissue were determined using ex vivo tissue impedance analysis methods.Results and Discussion: Our results demonstrate H-FIRE effective in BBB disruption and tissue ablation in a human brain model. Extent of BBB disruption, tissue ablation, and thermal damage is dependent on the number of bursts delivered, the energized time per burst, the applied voltage, as well as electrode configuration.