Background Recently introduced no-touch radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) has the potential to improve local tumor control. Purpose To evaluate midterm clinical outcomes of monopolar no-touch RFA in single HCCs 2.5 cm or smaller. Materials and Methods In this multicenter clinical trial (ClinicalTrials.gov: NCT03375281), participants were evaluated for eligibility from November 2017 to January 2019. Patients with single HCCs 2.5 cm or smaller planning to be treated with no-touch RFA were enrolled. The rate of successful no-touch RFA, defined as performing RFA without violation of the tumor itself, was recorded. Multivariable logistic regression analysis was used to determine associated factors for failure of no-touch RFA. Development of major complication after no-touch RFA was also recorded. Cumulative incidence of local tumor progression (LTP) and recurrence-free survival were estimated by using the Kaplan-Meier method. Results A total of 140 participants (mean age, 62 years ± 9 [standard deviation]; 106 men) were evaluated. No-touch RFA was successfully performed in 128 participants (128 of 140; 91.4%), and conversion to tumor puncture RFA was undertaken in 12 participants because of the lack of a safe access route. By using either no-touch RFA or conversion to tumor puncture RFA, all participants achieved technical success of RFA, which was defined as complete coverage of target tumor by ablation zone. Insufficient peritumoral parenchyma (<5 mm width around more than half portion of tumor; odds ratio, 74; 95% CI: 18, 309; P < .001) was the only significant predictive factor for failure of the no-touch technique. Among the 140 participants, LTP developed in two participants, and the estimated 1- and 2-year cumulative incidence of LTP was 0.7% and 1.6%, respectively. The estimated 1- and 2-year recurrence-free survival was 82.8% and 74.1%, respectively. Conclusion No-touch radiofrequency ablation was an effective and safe treatment method for small hepatocellular carcinomas (≤2.5 cm), with 1.6% of cumulative incidence of local tumor progression at 2 years. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Soulen and García-Mónaco in this issue.