Purpose To evaluate the safety and efficacy of microwave ablation (MWA) in patients with end-stage renal disease and secondary hyperparathyroidism. Materials and Methods The study protocol was approved by the human ethics review committee. Between March 1, 2014, and June 30, 2015, 51 patients (25 men, 26 women; mean age ± standard deviation, 53.1 years ± 12.9) were enrolled. All patients had at least one enlarged parathyroid gland and secondary symptomatic hyperparathyroidism, which was treated with ultrasonographically (US) guided MWA. The levels of intact parathyroid hormone, serum calcium, phosphorus, and alkaline phosphatase were compared before and after MWA. Paired-sample t tests and paired-sample Wilcoxon signed-rank tests were used to compare treatment outcomes before and after MWA. Results Complete ablation was achieved in all 96 glands in 51 of 120 patients with severe secondary hyperparathyroidism. The mean follow-up time was 11.1 months ± 3.3. The maximum diameter of the glands ranged from 0.5 cm to 4.8 cm (mean, 1.5 cm ± 0.6). The ablation time for each gland was 216.1 seconds ± 130.1. The mean serum intact parathyroid hormone, calcium, and phosphorus levels after MWA (400 pg/mL [400 ng/L; range, 151.3-629.0 ng/L], 2.33 mmol/L ± 0.23, and 1.54 mmol/L ± 0.43, respectively) were significantly lower than those before MWA (1203 pg/mL [1203 ng/L; range, 854.7-1694.5 ng/L], 2.53 mmol/L ± 0.24, and 1.97 mmol/L ± 0.50, respectively; P < .01), while the alkaline phosphatase levels did not change with MWA (P > .05). Ipsilateral recurrent laryngeal nerve injury was seen in one patient (2%). A hematoma developed during one procedure in one patient (2%) and was treated successfully with injection of thrombin. Conclusion US-guided MWA is safe and effective for destroying parathyroid gland tissue in patients with end-stage renal disease and severe secondary hyperparathyroidism. Further experience with the technique is clearly necessary. © RSNA, 2016.