Background and study aim :Hepatocellular carcinoma (HCC) is currently the fifth most common solid tumor worldwide and the third leading cause of cancer-related death. New therapeutic choices have been developed for HCC, including percutaneous ablation therapy, transarterial chemoembolization and molecular target therapy. Percutaneous acetic acid injection (PAI) and radio-frequency ablation (RFA) techniques became well-known procedures for controlling small HCC.The aim of this study was to compare the outcomes of per-cutaneous combined PAI and mitoxantrone injection versus RFA in the treatment of HCC.. Patients and Methods:This prospective study was conducted on 120 patients with 120 focal nodular HCCs of 4 cm or less between 2012 and 2014. They were randomly divided into 2 groups, the first group included 60 patients treated with PAI plus percutaneous intratumoral injection of mitoxantrone, and the second group included 60 patients treated with radio-frequency ablation. Clinical assessment, laboratory evaluation and triphasic CT studies were performed to all patients pre-treatment and at 1,3,6 and 12 months post treatment and complications were recorded. Results: The percentage of ablation in both groups at 1, 3, 6 and 12 months were 85%, 83.33%,78.34 and 73.33% in group I versus 88.33%, 88.3%, 85% and 81.66% in group II respectively with no statistical significant difference between the two groups. Percentage of ablation in small tumors was higher than large tumors in both groups. Side effects and complications are statistically higher in group II than group I. Conclusion: Combination of PAI and Mitoxantrone is comparable to radiofrequency ablation in treatments of HCCs with less frequent complications.