Percutaneous radiofrequency ablation (RFA) is able to destroy hepatocellular carcinoma (HCC) in a few sessions without major complications. We have previously shown that not only the combined use of percutaneous ethanol injection and RFA (PEI-RFA) but also injection of mixture of ethanol and lipiodol (PELIT) was useful for the treatment of HCC. In the present study, we further developed the combined use of PELIT and RFA through percutaneous or laparoscopic approach (PELI-RFA or LELI-RFA) and evaluated its usefulness. Nineteen nodules in 18 cases were treated with PELI-RFA or LELI-RFA. In the cases treated with LELI-RFA, no bleeding and no spilling milky fluid containing tumor cells were observed from the surface of ablated tumors. In the cases sufficiently treated with PELI-RFA or LELI-RFA, the mixture of ethanol and lipiodol was accumulated in the entire region of the tumor and low-density area was observed around the lipiodol deposit by computed tomography (CT). These delineations of coagulated area were helpful to evaluate the precise area of safety margin around the tumor treated with PELI-RFA or LELI-RFA. Furthermore, the total volume of coagulated necrosis significantly and positively correlated with the product of energy requirement for ablation and the volume of ethanol injected by PELI-RFA or LELI-RFA. Among the cases treated with PELI-RFA or LELI-RFA, local recurrence emerged only in one case in whom enough safety margin could not be achieved by PELI-RFA. Therefore, it is critical to evaluate whether enough safety margin could be obtained with RFA therapy, and PELI-RFA and LELI-RFA are helpful in visualizing the safety margin area.