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Background Interest in microwave ablation (MWA) and radiofrequency ablation (RFA) use for treating secondary hyperparathyroidism (SHPT) is rising; however, ablation outcomes in patients with SHPT are not well characterized. Purpose To assess the response of parathyroid hormone (PTH), calcium, phosphorus, and alkaline phosphatase (ALP) levels to US-guided parathyroid MWA and RFA and the safety of these treatments in participants with SHPT. Materials and Methods This prospective multicenter cohort study, conducted from September 2017 to March 2022, included participants with SHPT. The primary end point was the proportion of participants achieving the target PTH level (≤585 pg/mL). The secondary end points included PTH, calcium, phosphorus, and ALP levels before ablation and time points for follow-up assessments after ablation (2 hours, 1 day, 1 month, 3 months, and 6 months, and then every 6 months) and complications and technical success rates. Mixed-effects logistic regression models were used to identify factors associated with treatment failure. Results A total of 215 participants (median age, 53 years [IQR, 43-60 years]; 109 [50.7%] male participants) were evaluated, and 183 (85.1%) achieved target PTH levels. Compared with baseline levels, there was an 85.9%, 6.3%, 15.3%, and 37.4% reduction in PTH, calcium, phosphorus, and ALP levels at 24 months after ablation, respectively. For major complications, one (0.5%) participant experienced persistent hoarseness, and severe hypocalcemia (<1.87 mmol/L) was present in 74 (34.4%) participants. After adjustments, predictors associated with treatment failure included the preablation PTH level (adjusted odds ratio [OR], 3.78; 95% CI: 1.19, 12.04; P = .03), maximum tumor volume (adjusted OR, 5.02; 95% CI: 1.74, 14.53; P = .003), and number of glands ablated (adjusted OR, 0.32; 95% CI: 0.11, 0.98; P = .046). The prediction model showed good discrimination ability in the development and validation cohorts (area under the receiver operating characteristic curve, 0.78 [95% CI: 0.66, 0.90] and 0.73 [95% CI: 0.55, 0.91], respectively). Conclusion US-guided thermal ablation techniques were effective and safe treatments in participants with SHPT because they effectively reduced PTH, calcium, phosphorus, and ALP levels. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Gemmete in this issue.