Materials and Methods Patients population and study design We enrolled 149 patients (116 males and 33 females) who were diagnosed with HCC and underwent either CEUS-or conventional US-guided RFA. HCC was diagnosed based on either enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans, or Abstract: Objective To compare the value of contrast-enhanced ultrasound (CEUS) and conventional ultrasound (US) during radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC) ≥ 3.0 cm in diameter. Methods A total of 149 HCC patients treated with RFA guided by either CEUS or conventional US between January 2012 and June 2013 were retrospectively analyzed. Patients were divided into different groups based on the type of ultrasound guidance (CEUS or conventional US) and tumor volume (diameter < 3.0 or ≥ 3.0 cm). The progressionfree survival (PFS) and complete ablation rates were compared between groups, and risk factors for the PFS were investigated. Results Seventy four patients received CEUS-guided RFA, and conventional US was performed in 75 patients. Among patients with a tumor < 3.0 cm, the PFS and complete ablation rates were similar. However, for patients with a tumor ≥ 3.0 cm, those treated with CEUS had a significantly longer PFS (17.3 vs. 3.1 months, HR = 2.73; 95% CI, 1.28~5.81; P = 0.007) and higher complete ablation rates at 6-and 12-month post-treatment (87.5% vs. 57.7%, P = 0.042; 75.0% vs. 38.5%, P = 0.009, respectively) than those treated with conventional US-guided RFA. The type of treatment (P = 0.024) and maximum tumour size (P = 0.011) were both found to be independent factors associated with the PFS. Conclusion Compared with conventional US, CEUS is more effective for guiding RFA in patients with HCC ≥ 3.0 cm. CEUS-guided RFA could target HCC more accurately, and its ability to immediately detect any residual tumor during RFA might contribute to an increase in complete ablation rates and reduced progression.