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Objectives This study aimed to determine the performance of Sonazoid-based contrast-enhanced ultrasound (CEUS) in the microwave ablation (MWA) of primary hyperparathyroidism (pHPT). Methods Forty patients with pHPT were enrolled and treated with percutaneous ultrasound (US)-guided MWA assisted by CEUS. All patients underwent immediate CEUS examinations following MWA. On post-ablation day 1, patients who did not display a decrease in intact parathyroid hormone (iPTH) levels to the norm were examined by CEUS to evaluate an incomplete ablation. We compared the serum iPTH and calcium levels and the nodule volumes before and after MWA. The complications were evaluated during and after treatment. Results Immediately following MWA, CEUS demonstrated complete ablation with all 44 parathyroid nodules. On post-ablation day 1, five nodules in five patients displayed annular enhancement around the ablation zone on CEUS. The average maximum diameters of the nodules and the ablation zone were 1.09 ± 0.28 cm and 1.36 ± 0.23 cm, respectively. An ablation zone larger than the primary lesion (p < 0.05) generated a higher rate of complete ablation. Compared with pre-MWA, serum iPTH and calcium levels were significantly improved. Treatment success was achieved in 38 patients (95%). Hoarseness was a major complication in six patients (15%); however, it improved spontaneously within 1–4 months. We observed two recurrences (2/40, 5%) at 9 months and 11 months following MWA, respectively. Conclusion US-guided percutaneous MWA assisted by CEUS for pHPT is an effective and safe therapy. CEUS can avoid operative failure and improve the cure rate.