The purpose of this study was to prospectively evaluate the safety and effectiveness of radiofrequency ablation (RFA) by using a multiple-electrode switching system to treat unresectable medium-large (3.1–6.0 cm) HCC nodules. RFA using a multiple-electrode switching system was performed for HCC nodules with size > 3.0 < 6.0 cm in nonsurgical candidates. Two electrodes were consecutively placed for 3.1–4.0 cm tumours, and three electrodes for 4.1–5.9 cm tumours, with a 2.0–2.5 cm spacing. The power was switched from one electrode to the next automatically when the impedance reached 30 Ω above the baseline level. 25 patients (M/F = 9/16; median age 76 years, range 61-84) with liver cirrhosis (20 HCV-positive) in Child's Class A (22 cases) and B (3 cases) and 26 HCC nodules (median diameter 4.0 cm; range 3.2–5.5 cm) underwent treatment in 25 sessions from 2013 and 2018. Therapeutic effectiveness was assessed through CT or MRI exam at 30–40 days post-ablation. No procedure-related death or major complications occurred. Complete ablation was obtained in all nodules (100%). At a median follow up of 30 months, local tumor progression occurred in five out of 26 nodules (19.2%). Overall survival at 4 years was 49%. RFA with a multiple-electrode switching system may be a safe, quick and effective therapeutic option for treatment of 3.1-6.0 cm unresectable HCC tumours. RFA with multiple electrodes provides favourable clinical results in patients with medium-large HCC nodules who are not suitable for surgery [ABSTRACT FROM AUTHOR]