Background: No direct prospective studies comparing laser ablation (LA) and radiofrequency ablation (RFA) for debulking benign non-functioning thyroid nodules (BNTNs) exist. We aimed at comparing the efficacy and safety of both techniques in patients with solid or predominantly solid BNTN. Methods: This six-month, single-use, randomized, open-label, parallel trial compared the following primary endpoints between the RFA and LA groups six months after treatment: (i) nodule volume reduction expressed as a percentage of nodule volume at baseline; (ii) proportion of nodules with more than 50% reduction (successful rate). We enrolled subjects with a solitary BNTN or dominant nodule characterized by pressure symptoms/cosmetic problems or patients without symptoms who experienced a volume increase >20% in one year. Nodules underwent core needle biopsy for diagnosis. Patients were randomly assigned (1:1) to receive LA or RFA. Safety was assessed in all randomly assigned participants. Results: Sixty patients were randomly assigned to receive either RFA or LA (1:1) between January 2016 and November 2018. Both groups were similar in basal nodule volume, thyroid function, histology, symptoms/ cosmetic score, and procedure time. At six months, the nodule volume reduction was 64.3% (95% confidence interval, CI 57.5-71.2) in the RFA group and 53.2% ([CI 47.2-95.2]; p = 0.02) in the LA group. This effect was also confirmed in the linear regression model adjusted for age, baseline volume, and proportion of cellular component (LA vs. RFA percent change Delta =-12.8, p = 0.02). No significant difference was observed in success rate six months after treatment (RFA vs. LA: 86.7% vs. 66.7%, p = 0.13) or in thyrotropin level between the groups. Although improved, no significant difference was observed between RFA and LA for compressive symptoms (RFA: 2.13 vs. 3.9, p < 0 $ 001; LA: 2.4 vs. 3.87, p < 0.001) and cosmetic score (RFA: 1.65 vs. 2.2, p < 0.001; LA: 1.85 vs. 2.2, p < 0.001). The adverse event rates (local pain, dysphonia, thyrotoxicosis, fever, hematoma) were 37% (n = 11) and 43% (n = 13) for RFA and LA, respectively, with no requirement for hospitalization. Conclusion: Although the success rate was similar in the RFA and LA groups, RFA achieved a significantly larger nodule volume reduction at six months.