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New therapeutic choices have been developed for hepatocellular carcinoma, including percutaneous ablation therapy, transarterial chemoembolization, radiation therapy and molecular target therapy. Ablation of liver tumors is currently the main alternative to liver resection. This work aimed at comparing percutaneous combined local injection of ethanol and mitoxantrone versus percutaneous radiofrequency ablation in the treatment of Hepatocellular Carcinoma. This study included 124 patients with hepatocellular carcinoma, they were randomly divided into two groups; group I (64 patients) treated with local injection of ethanol plus mitoxantrone. Group II (60 patients) treated with radiofrequency ablation. Clinical assessment, laboratory evaluation and CT studies were performed to all patients prior to treatment and at 1, 3, 6, and 12 months' post treatment. The percentage of ablation in both groups at 1, 3, 6 and 12 months were 81.3%, 81.3%,76.6 and 71.9% in group I respectively versus 88.3%, 88.3, 85%% and 81.7% in group II respectively with no statistical significant difference between the two groups. Percentage of ablation in small tumors is higher than large tumors in both groups. Side effects and complications are statistically higher in group II than group I. Combination of percutaneous local injection of ethanol and mitoxantrone is comparable to radiofrequency ablation with less frequent complications in the treatment of Hepatocellular Carcinoma when surgical resection or liver transplantation is not amenable or available. [Med-Science 2016; 5(4.000): 948-56]