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The use of Radiofrequency thermoablation (RFA) for treating large thyroid nodules is limited by the modest efficiency of the available systems in terms of volume of the ablation zones (AZs). This increases the risk of incomplete ablation of the nodule. Systems employing perfused electrodes have been developed to increase the volume of the AZ. Aim of this study is to compare the size of the AZ induced by RFA systems using internally cooled perfused vs. non-perfused electrodes in swine thyroids. RFAs were performed on 40 freshly isolated swine thyroids using both systems. The perfused system was tested using 0.9% saline, 7% and 18% hypertonic saline solutions. Energy delivery to the tissue was stopped when tissue conductivity dropped (real life simulations) and after an established time of 20 seconds (controlled duration). Following RFA, thyroids were transversally and longitudinally cut. Photographs were taken for macroscopic morphometry of the ablated zones before and after formalin fixation, to evaluate tissue shrinkage. Microscopic morphometry was performed on PAS stained sections. In real life simulation experiments, gross morphometry revealed that AZs produced with electrodes perfused using 7.0% saline are larger compared to isotonic saline. Microscopically, all the conditions tested using the perfused system produced larger AZs compared to non-perfused system after 20 seconds of RFA. In conclusion, the perfusion with 7.0% NaCl solution increased the electrical conductivity of the tissue in real life simulations, resulting in larger ablated areas compared to the use of isotonic saline.