Our purpose was to compare the effects of percutaneous radiofrequency ablation (RFA) combined with percutaneous ethanol injection (PEI) on the extent of ablation in in vivo rabbit liver tissue as compared with either therapy alone. Twenty-two New Zealand white rabbits were included in this study and allocated into three groups: group A: conventional RFA (n = 6); group B: PEI (n = 6): group C: combined RFA and PEI (n = 10). For combined RFA and PEI, under ultrasound guidance, 1 mL of absolute ethanol was injected into the target area of the liver parenchyma through a 21-gauge Chiba needle before performing RFA. RFA was performed using a 17-gauge internally cooled electrode with 1-cm active tip, and RF energy (30 W) was applied for 3 minutes, with or without ethanol injection. After RFA or PEI, contrast-enhanced computed tomography and CT-pathologic correlation were performed. The short-axis and long-axis diameters of thermal lesions of each group were compared. All procedures were technically successful and a total of 38 lesions were produced. The mean short-axis and long-axis diameter of the coagulation necrosis in rabbits of group C (combination of RFA and PEI), were significantly larger than those of other groups: group A: 10.3 +/- 2 mm and 11.4 +/- 2 mm: group B: 3.1 +/- 1 mm and 4.3 +/- 2 mm: group C: 12.8 +/- 3 mm and 17.8 +/- 6 mm (p < 0.05). On contrast-enhanced CT scan, the lesions of rabbits of the group C appeared to be more frequently irregular compared to those of group A (20% in group A vs. 67% in group C). There were three complications including two localized hematomas and one cardiopulmonary failure. Combined RFA and PEI could increase the dimension of coagulation necrosis without increasing complications and therefore, may be successfully used for treating larger lesions.