Background Microwave ablation is effective for severe secondary hyperparathyroidism, but the difference in efficacy between microwave ablation and parathyroidectomy remains unclear. In this multicenter retrospective cohort study, we compared the long-term clinical efficacy of microwave ablation and parathyroidectomy for severe secondary hyperparathyroidism undergoing hemodialysis. Materials and methods The patients were divided into microwave ablation and parathyroidectomy groups. The primary endpoint was the proportion of patients with intact parathyroid hormone (iPTH) concentrations within the target range (100-600 pg/mL) during the efficacy assessment phase. The secondary endpoints were (i) differences in iPTH concentrations over time between the two groups, and (ii) decreases in iPTH concentrations over time in the two groups. Results Microwave ablation was performed in 47/92 patients and parathyroidectomy in 45/92. Primary endpoint: iPTH concentrations within the target range were achieved during the efficacy assessment phase in 26/47 patients (55.3%) and in 14/45 (31.1%) patients in the microwave ablation and parathyroidectomy groups, respectively (p = .02). Secondary endpoints: (i) Mean iPTH concentrations during the efficacy assessment phase were significantly higher in the microwave ablation versus parathyroidectomy groups (649 +/- 519 pg/mL versus 136 +/- 228 pg/mL, respectively; p < .01). (ii) Mean decrease in iPTH concentration from baseline was 725 +/- 605 pg/mL versus 1369 +/- 478 pg/mL in the MWA versus parathyroidectomy groups, respectively (p < .01). Conclusions Ultrasound-guided percutaneous microwave ablation provides higher iPTH target-achieving rates than parathyroidectomy in patients with severe secondary hyperparathyroidism undergoing hemodialysis.