We thank Dr. Futyma for his attention to our manuscript 1 and the interesting discussion he provides in his letter 2 . This gives us the opportunity to further highlight the proposed non-thermal character of irreversible electroporation (IRE). Displacement of ohmic currents inside a tissue, a medium with an intrinsic impedance, will anytime, to some extent, produce a local temperature increase by Joule heating. This issue exists whether IRE is elicited by DC pulses or AC bursts. IRE ablation is considered non-thermal only when finely tuned to induce non- necrotic selective cellular death. As we highlighted in our review, the border is not clearly defined, but sparing adjacent heat-sensitive structures or tissues (especially extracellular matrix and blood vessels) is a relevant aim. Thermal damage will occur in muscle immediately, at temperatures above 50C 3 . This value is considered a maximal threshold to avoid thermal damage in tumor IRE ablation, as reported in in vitro 4 and in vivo 5 studies. Discussing the detailed work by Faroja et al 6 , this shows that elevated temperature levels can be generated due to IRE energy application on liver. Nevertheless, even in this study there is an identified non-thermal working range (measured temperature between 34-42C), detected by peaking of caspase 3, a known apoptotic marker. The study of Meyer et al. 7 is mentioned, as this shows that the use of defibrillating shocks produces skin erythema, with 5 applications at 360J. The application of defibrillating shocks is heavily dependent on skin electrode contact and energy delivered can be over two orders of magnitude stronger than a single IRE pulse. Considering, simplistically, an initial tissue-electrode resistive impedance of 100 Ohm 8 , a 3000 V DC application for 100 µs will cause an energy delivery of 9 J, requiring 200 applications to deliver the same amount of energy delivered in the mentioned study. In a recent work by Neven et al., a 200J single defibrillating shock was delivered from a decapolar circular catheter, using an external reference patch to ablate pulmonary veins sleeves. In this scenario, only mild intimal hyperplasia was reported, together with successful isolation 9 . Whether this proliferation is induced by hybrid thermo-electric effect is not clear, yet it does not hamper the therapeutic effects. It must be taken into consideration that IRE energy delivery, given the same electrical parameter, is also affected by the active electrode area and the proximity between active and reference electrode, as these parameters affect the tissue- electrode impedance. Therefore, it is clear how fundamental is to tune the IRE application parameters (e.g., voltage, pulse width and inter-pulse distance) and physical specifications (e.g., electrode area, reference proximity) to achieve the optimal efficacy and benefits of this approach, among the others providing a “cool” non-thermal method to overcome the limits of purely thermal-based ablation methods.