Background To compare the short-term clinical outcomes of ultrasound-guided microwave ablation (MWA) and parathyroidectomy (PTX) for severe secondary hyperparathyroidism(SHPT). Methods In a prospective multi-center study, we compared the outcomes of MWA and PTX for severe SHPT. The outcome measures were case rate of successful treatment, improvement of clinical symptoms, incidence of complications, and differences in treatment parameters and costs between the two groups. Results A total of 167 eligible patients were included in the study, of which 79 underwent MWA and 88 underwent PTX. There was no significant difference in rate of successful treatment between the MWA and PTX groups (chi(2)=2.299, p = 0.125). However, the MWA group showed significantly lower range of intact parathyroid hormone (iPTH) decrease than the PTX group (t=-2.352, p = 0.023). Postoperative clinical symptoms improved in both groups, with no significant difference between the two groups (p > 0.05). Postoperative hypocalcemia was significantly more common in the PTX group (p < 0.05). The operative time, incision and postoperative pain of the MWA group were significantly better than those of the PTX group (p < 0.05), while postoperative recurrent laryngeal nerve injury and hematoma showed no significant difference between the two groups (p > 0.05). The cost of MWA was significantly less than PTX (p = 0.000). Conclusions Both MWA and PTX are effective and safe for severe secondary hyperparathyroidism. PTX is more thorough and traumatic, while MWA is minimally invasive and postoperative iPTH is more consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendation.