AbstractIrreversible electroporation is a fast-growing liver ablation technique. Although safety has been well documented in small ablations, our aim is to assess its safety and feasibility when a large portion of liver is ablated. Eighty-seven mice were subjected to high voltage pulses directly delivered across parallel plate electrodes comprising around 40% of mouse liver. One group consisted in 55 athymic-nude, in which a tumor from the KM12C cell line was grown and the other thirty-two C57-Bl6 non-tumoral mice. Both groups were subsequently divided into subsets according to the delivered field strength (1000 V/cm, 2000 V/cm) and whether or not they received anti-hyperkalemia therapy. Early mortality (less than 24 hours post-IRE) in the 2000 V/cm group was observed and revealed considerably higher mean potassium levels. In contrast, the animals subjected to a 2000 V/cm field treated with the anti-hyperkalemia therapy had higher survival rates (OR = 0.1, 95%CI = 0.02–0.32, p < 0.001). Early mortality also depended on the electric field magnitude of the IRE protocol, as mice given 1000 V/cm survived longer than those given 2000 V/cm (OR = 4.7, 95%CI = 1.8–11.8, p = 0.001). Our findings suggest that ionic disturbances, mainly due to potassium alterations, should be warned and envisioned when large volume ablations are performed by IRE.