Objectives To prospectively investigate the efficacy and safety of ultrasound (US)-guided microwave ablation (MWA) and radiofrequency ablation (RFA) for primary hyperparathyroidism (PHPT). Methods We performed a prospective multicenter study of MWA and RFA for PHPT between August 2017 and October 2020 at five centers. Laboratory testing was performed pre- and post-ablation and followed for at least 6 months. The primary outcome was the cure rate. Secondary outcomes were complications and dynamic changes in serum levels of PTH, calcium, phosphorus, and ALP after ablation. Results A total of 132 participants (mean age, 57.33 +/- 13.90 years), with 141 parathyroid nodules (median maximal diameter, 1.55 cm) undergoing either MWA or RFA, were enrolled in the study. The technique success rate was 99.29% (140/141). The follow-up period was 6-36 months (median, 12 months). The cure rate was 80.30% (106/132). Pre-ablation PTH level was the independent factor associated with cure rate (Odds ratio (OR), 0.22; 95% CI, 0.07-0.69; p = 0.0090). There was no difference in cure rate between the MWA group and the RFA group (80.22% vs. 80.49%, p = 0.971). The only main complication was hoarseness (5.30%). Conclusions US-guided MWA and RFA for PHPT is an effective and safe procedure in the treatment of PHPT. Pre-ablation PTH level is the key factor affecting the cure rate after MWA and RFA.