Background and study aim: Radio-frequency ablation (RFA) has attracted the greatest interest because of its effectiveness and safety. However, complete tumor necrosis rate with RFA for tumors larger than 5 cm is less favorable. Acetic acid, which has the ability to penetrate cells with the property of extracting collagen and dissolving lipids, has a stronger killing effect on hepatocytes than ethanol. The aim of this study was to compare two percutaneous combined therapies, RFA plus percutaneous ethanol injection (PEI) and RFA plus percutaneous acetic acid injection (PAI) in hepatocellular carcinoma (HCC) treatment in patients having single focal lesions more than five and up to seven cm in diameter. Patients and Methods: The patients were selected according to the triphasic CT scanning characteristics of HCC. They were randomly allocated into 2 groups: GI included 30 patients who were candidates for 1 setting of RFA then PEI in the same setting. GII included 30 patients ;they were ablated by 1 setting of RFA with 2 overlaps to decrease the size of the remaining unablated areas, then PAI in the same setting. Results: Evaluation of the response one month later using triphasic CT showed significant better responses in GII compared to GI (83.3% vs 60%) with P value <0.05. The response 3 months later was not changed significantly compared to the response after one month of the procedure (56.7% in GI and 80% in GII) Conclusion: Ablation of inoperable large HCC 5.1-7cm can be done with combined techniques. RFA plus acetic acid was compared to RFA plus ethyl alcohol. Complete ablation was superior when acetic acid was used.