Purpose To assess the feasibility, efficacy, and safety of ultrasound (US)-guided microwave ablation (MWA) for the treatment of papillary thyroid cancer (PTC) located in the thyroid isthmus. Materials and methods Thirty-four patients (mean age, 43 +/- 11 years; 26 women) with isthmic PTC treated with MWA between June 2014 and September 2020 were included in this retrospective study. The follow-up time after MWA was 17 +/- 9 months (range, 8-50 months). Changes in thyroid function, parathyroid function, and tumor size were evaluated, along with the rates of tumor disappearance and complications. Results The treatment was technically feasible and successfully completed in all 34 patients (100%). Measures of thyroid function (i.e. serum triiodothyronine, free thyroxine, and thyrotropin) and parathyroid function (i.e. serum calcium and intact parathyroid hormone) showed no changes from pretreatment levels at 1, 3, and 6 months after MWA (p > 0.05 for all). Tumor size was found to be increased at 1 and 3 months after MWA compared with before MWA (p < 0.05). However, the tumor sizes measured at 6, 9, 12, and 18 months after MWA were smaller than the pretreatment sizes (p < 0.05 for all). In 24 cases (70.6%), the tumors completely disappeared on US examination. Five cases (2.9%) experienced side effects from MWA treatment, but no major or minor complications were recorded. Conclusion The results of this study demonstrate that US-guided MWA is a feasible, effective, and safe treatment option for selected patients with PTC located in the thyroid isthmus.