Electroporation or electropermeabilization is a technique that enables transient increase in the cell membrane permeability by exposing cells to pulsed electric field. However, the molecular mechanisms of the long-lived cell membrane permeability, which persists on the minutes time scale after the pulse treatment, remain elusive. Experimental studies have suggested that lipid peroxidation could present a mechanism of this prolonged membrane permeabilization. In this study we make the first important step in quantifying the possible contribution of lipid peroxidation to electropermeabilization. We use free energy calculations to quantify the permeability and conductance of bilayers, containing an increasing percentage of hydroperoxide lipid derivatives, to sodium and chloride ions. We then compare our calculations to experimental measurements on electropermeabilized cells. Our results show that the permeability and conductance increase dramatically by several orders of magnitude in peroxidized bilayers. Yet this increase is not sufficient to reasonably account for the entire range of experimental measurements. Nevertheless, lipid peroxidation might be considered an important mechanism of prolonged membrane permeabilization, if exposure of cells to high voltage electric pulses leads to secondary lipid peroxidation products. Our analysis calls for experimental studies, which will determine the type and amount of lipid peroxidation products in electropermeabilized cell membranes. •Na and Cl ions permeability of peroxidized lipid bilayers is investigated using Unified Free Energy Dynamics simulations.•The contribution of lipid peroxidation to electropermeabilization is quantitatively assessed.•High amounts of peroxidized lipids increase the bilayers permeability and conductance by several orders of magnitude.•Hydroperoxide lipid derivatives are not permeable enough to account for the measured electropermeabilization of cells.