Liver cancer is a major health concern worldwide. Radiofrequency ablation is a safe treatment option that can be guided by either ultrasound, computer tomography (CT), or fluoroscopy. Although ultrasound-guided radiofrequency ablation is commonly used in clinical practice, radiofrequency ablation guided by CT is more precise but requires more time and does not offer real-time monitoring, which may result in complications such as pneumothorax or organ damage. In this study, we investigated the effect of ultrasound, CT, and combined ultrasound/CT guidance on patient survival and complication development. A total of 982 radiofrequency ablation sessions conducted on 553 patients were analyzed. Clinical outcomes were assessed during follow-up to determine the survival and recurrence rates of malignant tumors. Overall, the three guidance approaches exhibited significant differences in terms of tumor size, number, complication development, and treatment duration. However, no significant differences were observed in survival rate. A comparison of the effect of CT guidance and ultrasound guidance on complication development revealed a higher odds ratio for CT guidance in some cases. A comparison of combined ultrasound/CT guidance and ultrasound guidance revealed nonsignificant differences in complication development. A comparison of CT guidance and combined ultrasound/CT guidance revealed a higher odds ratio for CT guidance in some cases. Radiofrequency ablation is a safe and effective treatment for liver tumors. However, CT has an increased incidence of complications. Combined ultrasound/computer tomography guidance is recommended for patients with multiple or large tumors or tumors near the hepatic dome or diaphragm.