Objective: To assess the efficacy and safety of ultrasound (US)-guided radiofrequency ablation (RFA) in patients with primary hyperparathyroidism (PHPT). Materials and Methods: This prospective study enrolled 39 participants (14 male, 25 female; mean age, 59.5 ± 15.3 [range, 18-87] years) between September 1, 2018, and January 31, 2021. All participants had parathyroid lesions causing PHPT, proven biochemically and through imaging. The imaging features of the PHPT nodules, including the shape, margin, size, composition, and location, were evaluated before treatment. Serum intact parathyroid hormone, calcium, and phosphorus levels; parathyroid nodule volume; and PHPT-related symptoms were recorded before and after treatment. We calculated the technical success, biochemical cure, and clinical cure rates for these patients. Complications were evaluated during and after the ablation. Results: Complete ablation was achieved in 38 of the 39 nodules in the 39 enrolled participants. All the patients were treated in one session. The technical success rate was 97.4% (38/39). The mean follow-up duration was 13.2 ± 4.6 (range, 6.0-24.9) months. At 6 and 12 months post-RFA, the biochemical cure rates were 82.1% (32/39) and 84.4% (27/32), respectively, and the clinical cure rates were 100% (39/39) and 96.9% (31/32), respectively. Only 2.6% (1/39) of the patients had recurrent PHPT. At 1, 3, 6, and 12 months after technically successful RFA, 44.7% (17/38), 34.3% (12/35), 15.8% (6/38), and 12.5% (4/32) of participants, respectively, had elevated eucalcemic parathyroid hormone levels. Recurrent laryngeal nerve paralysis occurred in 5.1% (2/39) of the patients, who recovered spontaneously within 1-3 months. Conclusion: US-guided RFA was effective and safe for PHPT patients. RFA may be an alternative treatment tool for patients who cannot tolerate or refuse to undergo surgery.