Prognostic factors such as large tumor size and viral factors have not been fully evaluated in hepatocellular carcinoma (HCC) following radiofrequency ablation (RFA). We aimed to investigate prognostic factors of RFA by a nationwide cohort study. Based on Taiwan National Health Insurance Research Database, 50,791 patients with newly diagnosed HCC were screened between July 2004 and December 2011. After excluding combination therapy, vascular invasion, extrahepatic metastasis or follow-up period less than 6 months, 2,261 patients who received RFA as curative therapy were identified. Cumulative incidences of and hazard ratios (HRs) for HCC recurrence and patient mortality were analyzed. With a median follow-up of 33.6 months, 5-year HCC recurrence and overall survival rates were 64.0% (95% confidence interval (CI): 61.5–6.5%) and 52.6% (95% CI: 49.7–55.5%), respec-tively. On multivariate analysis, tumor size >5 cm (HR 1.73; 95% CI, 1.35-2.23), hepatitis B virus infection (HR 1.34; 95% CI, 1.17-1.54), hepatitis C virus infection (HR 1.46; 95% CI, 1.26-1.68) and cirrhosis (HR 1.24; 95% CI, 1.09-1.42) were associated with an increased risk of HCC recurrence, and NSAIDs or aspirin use (HR 0.86; 95% CI, 0.76-0.97) were associated with a decreased risk. In addition, increased age (HR 1.02; 95% CI, 1.01-1.03), tumor size >5 cm (HR 1.61; 95% CI, 1.21-2.16), alcoholic liver disease (HR 1.38; 95% CI, 1.01-1.88), cirrhosis (HR 1.50; 95% CI, 1.26-1.79), liver decompensation (HR 1.84; CI, 1.49-2.27) and diabetes (HR 1.50; CI, 1.23-1.83) were associated with an increased risk of patient mortality. Conclusion: HCC patients with prognostic factors such as tumor size >5 cm should be carefully selected for RFA. Chronic viral infection was associated with tumor recurrence after RFA, and antiviral treatment could be further studied.