For the treatment of small hepatocellular carcinoma (HCC), radiofrequency ablation (RFA) is in some centers considered a first-line therapeutic option. However, such a strategy is still under debate with regard to tumor and patient characteristics. In this single-center study we assessed the 5-year survival and prognosis factors in 235 consecutive patients with cirrhosis (Child-Pugh A/B: 205/30) who received RFA as first-line treatment for up to three HCC <5 cm (307 tumors; mean diameter: 29 ؎ 10 mm; 53 multinodular forms). Among these patients, 67 satisfied the criteria for resection according to the Barcelona Clinic Liver Cancer. Complete ablation was obtained in 222 patients (94%). Overall, 337 RFA sessions were performed including iterative RFA for recurrence. Major complications occurred in three patients (0.9%), including one treatmentrelated death. After 27 ؎ 20 months of mean follow-up, local or distant, or both, tumor recurrence occurred in 16, 88, and 11 patients, respectively. Twenty-nine patients underwent transplantation and were removed from the study at this point. Overall 5-year, recurrence-free, and tumor-free (including results of iterative RFA) survival rates were, respectively, 40%, 17%, and 32%. The overall 5-year survival rate was 76% for operable patients. Factors associated with overall survival were prothrombin activity (hazard ratio [HR] ؍ 0.97, 0.96-0.98; P < 0.0001) and serum levels of ␣-fetoprotein (AFP) (HR ؍ 1.02, 1.02-1.02; P < 0.0001), and factors associated with tumor recurrence were multinodular forms (HR ؍ 2.34; 1.52-3.6; P ؍ 0.0001) and serum AFP levels (HR ؍ 1.015, 1.014-1.016; P ؍ 0.015). Tumor size was associated with local recurrence but not with overall and tumor-free survival. Conclusion: RFA is a safe and effective first-line treatment of HCC up to 5 cm in diameter, especially for patients with a single tumor, a low serum AFP level, and well-preserved liver function. (HEPATOLOGY 2009;50:1475-1483.