Radiofrequency ablation (RFA) is an effective modality for the treatment of hepatocellular carcinoma (HCC), because it can induce large coagulated necrosis in a few sessions. We have recently reported that the combination therapy of percutaneous ethanol injection (PEI) with RFA (PEI-RFA) created enhancement of coagulated necrosis compared with RFA alone. In the present study, we adopted PEI-RFA for the treatment of HCCs located in the regions that are difficult to treat with RFA alone. Five patients with biopsy-proven HCC and liver cirrhosis underwent PEI-RFA therapy. In these patients, HCCs were located beside the gallbladder, inferior vena cava or portal vein or kidney, or immediately under the diaphragm. Prior to RFA, 99.5% ethanol was injected into the region of HCC located in the regions where RFA energy appears to be difficult to reach. In all cases, HCC was totally coagulated by PEI-RFA. Injecting ethanol prior to RFA therapy caused no major side effects. These results indicate that PEI-RFA may be effective for the treatment of HCCs located in the regions that are difficult to treat with RFA alone as well as large-sized HCCs.