To establish a preoperative protocol for ultrasonographically guided percutaneous radiofrequency (RF) ablation of large liver tumors that is based on mathematic models and clinical experience and to evaluate the role of this protocol in RF ablation. A regular prism and a regular polyhedron model were used to develop a preoperative protocol for liver tumor ablation. This protocol enabled the authors to minimize the number of ablation spheres, optimize the overlapping mode, and determine the electrode placement process. One hundred ten patients with 121 liver tumors were treated by using this protocol. Sixty-nine patients had 74 hepatocellular carcinomas (HCCs), and 41 had 47 metastases to the liver (ie, metastatic liver carcinomas [MLCs]). Patients underwent follow-up helical computed tomography (CT) 1 month and every 2-3 months after RF ablation. Ablation was considered a success if no contrast enhancement was detected in the treated area on the CT scan obtained at 1 month. A total of 536 ablations were performed in the 121 tumors. The ablation success rate was 87.6% (106 of 121 tumors); the local recurrence rate, 24.0% (29 of 121 tumors); and the estimated mean recurrence-free survival, 17.1 months. Twenty-five patients underwent 38 re-treatments for local tumor recurrence. Major complications occurred in seven patients. Of these patients, only one, who had a tumor close to the colon, had a colon perforation 1 week after RF and required surgical intervention. The described protocol for treatment of large tumors had a success rate of 87.6% and a local recurrence rate of 24.0%. Copyright RSNA, 2004