Abstract Application of radiofrequency ablative techniques to thyroid disease could result in treatments that are nontoxic, thyroid sparing, and minimally invasive. The purpose of this pilot study was to evaluate the safety of radiofrequency ablation (RFA) of thyroid tissue in a porcine model. Eight euthyroid Yorkshire pigs weighing 35–45 kg were randomized to control or ultrasound-guided central thyroid RFA at three doses: 500, 1000, or 2000 J. Animals were evaluated for signs of recurrent laryngeal nerve damage. Serum thyroid hormone levels were assayed in all animals at baseline and postprocedurally at 24 h, 96 h, and weekly for 6 weeks. Total thyroidectomy was performed 6 weeks post-RFA. None of the animals in this study suffered pathologic recurrent laryngeal nerve damage. Free T4 levels were not elevated in any animal at any time point in this study. Mean weight gain among these rapidly growing pediatric pigs was 18 kg in the 6 weeks following RFA or control procedure and was similar between groups. Post-RFA histology revealed localized necrosis with normal appearing surrounding thyroid tissue. Ultrasound-guided RFA in the thyroid gland is feasible and safe. Application of up to 2000 J of radiofrequency energy in normal thyroid tissue does not cause thyrotoxicosis. Given the proven track record of radiofrequency ablative techniques in other tumor types, clinical trials evaluating the efficacy of RFA technology in benign human thyroid disease are warranted.