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Irreversible electroporation (IRE) is a nonthermal ablation modality employed to induce in situ tissue-cell death. This study sought to evaluate the efficacy of a novel high-frequency IRE (H-FIRE) system to perform hepatic ablations across, or adjacent to, critical vascular and biliary structures. Using ultrasound guidance H-FIRE electrodes were placed across, or adjacent to, portal pedicels, hepatic veins, or the gall bladder in a porcine model. H-FIRE pulses were delivered (2250 V, 2-5-2 pulse configuration) in the absence of cardiac synchronization or intraoperative paralytics. Six hours after H-FIRE the liver was resected and analyzed. Nine ablations were performed in 3 separate experimental groups (major vessels straddled by electrodes, electrodes placed adjacent to major vessels, electrodes placed adjacent to gall bladder). Average ablation time was 290 ± 63 seconds. No electrocardiogram abnormalities or changes in vital signs were observed during H-FIRE. At necropsy, no vascular damage, coagulated-thermally desiccated blood vessels, or perforated biliary structures were noted. Histologically, H-FIRE demonstrated effective tissue ablation and uniform induction of apoptotic cell death in the parenchyma independent of vascular or biliary structure location. Detailed microscopic analysis revealed minor endothelial damage within areas subjected to H-FIRE, particularly in regions proximal to electrode insertion. These data indicate H-FIRE is a novel means to perform rapid, reproducible IRE in liver tissue while preserving gross vascular/biliary architecture. These characteristics raise the potential for long-term survival studies to test the viability of this technology toward clinical use to target tumors not amenable to thermal ablation or resection.