Compared with microwave ablation (MWA), percutaneous radiofrequency ablation (RFA) and laser ablation (LA) have been recommended as minimally invasive treatments for patients with symptomatic benign thyroid nodules (BTNs) because of the large number of clinical applications. This prospective multicenter study sought to evaluate the clinical outcomes of RFA and MWA for BTNs. In eight participating institutions, the total number of 1252 patients treated by RFA and MWA were 649 ones with 687 BTNs and 603 ones with 664 BTNs, respectively. The clinical outcomes including the nodular maximal diameter reduction ratio (MDRR), the nodular volume reduction ratio (VRR), and the incidence of complications were compared to evaluate the efficacy and safety of the two techniques. The results for the nodular MDRR and VRR in the RFA group were significantly better than those in the MWA group at 6 months and later follow-up, and the major complication rates of 4.78% and 6.63% in RFA and MWA groups showed no statistically significant differences. In conclusion, both RFA and MWA are safe and effective techniques for selected patients with symptomatic BTNs. The achieved MDRR and VRR in the RFA group were greater than those in the MWA group at 6 months and later follow-up.