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The purpose of this study was to evaluate the efficacy of unenhanced cone-beam computed tomography (CBCT) performed at the end of drug-eluting bead transarterial chemoembolization (DEB-TACE) in predicting HCC nodules’ early radiologic response to treatment, assessed using mRECIST criteria with a 30–60 day four-phase contrast-enhanced CT follow-up. Fifty-nine patients (81 lesions) subjected to DEB-TACE as exclusive treatment for HCC lesions (naive/relapse) between February 2020 and October 2021 were prospectively enrolled. In a post-interventional unenhanced CBCT procedure, two experienced radiologists evaluated for each lesion the overall intensity of the contrast media deposit, the homogeneity of the enhancement, and the presence of smooth and complete margins. The univariate analysis found that lesions with complete response (CR+) had a significantly higher incidence of clear and complete margins than CR− lesions (76.9% vs. 17.2%, p = 0.003) and a higher intensity score (67.3% vs. 27.6%, p = 0.0009). A Dmax