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Introduction This study was performed to determine the feasibility and safety of creating superficial histotripsy treatment in a live porcine thyroid model. Methods The porcine thymus comparable in size, shape and location to the human thyroid was used for this study. This model has been used for thyroid surgery studies due to the diminutive size of the porcine thyroid. Four female swine underwent a total of eight histotripsy treatments performed with a prototype therapy system (HistoSonics, Inc., Ann Arbor, MI). Two treatments were performed in each animal: a spherical 1.0 × 1.0 × 1.0 cm and ovoid 1.0 × 1.0 × 2.0 cm treatment zones. MRI immediately post-procedure was evaluated for histotripsy treatment zone size and imaging appearance, followed immediately by sacrifice. Tissue was then reviewed for percent cellular destruction and precision. Results Treatment zones measured on post treatment MRI were similar to prescribed volumes (spherical = 0.60 (+/− 0.11) cm3, ovoid = 1.23 (+/− 0.40) cm3, p > 0.05 vs. prescribed). MRI demonstrated well demarcated treatment zones and imaging findings consistent with cellular destruction. Histology demonstrated sharp transitions to normal tissue (mean 0.33 (+/− 0.13) cm), and high degrees of cellular destruction (mean 76% (+/− 12.5), range of 50–100%) in the treated tissue. Edema within the overlying muscle was seen in 2/8 treatments. Conclusion Histotripsy is capable of safely creating precise histotripsy treatments within the superficial neck of a porcine thyroid model without evidence of considerable complications.