Background. There is controversy regarding whether patients with single hepatocellular carcinoma (HCC) should be offered radiofrequency ablation (RFA) as a first-line treatment option. Thus, this study compared overall survival after surgical resection (SR) and RFA for single HCC. Methods. The Surveillance, Epidemiology, and End Results (SEER) database was used for this retrospective study. The study included 30- to 84-year-old patients diagnosed with HCC from 2000 to 2018. Selection bias was reduced via propensity score matching (PSM). The study compared the overall survival (OS) and cancer-specific survival (CSS) of patients with single HCC who were treated with SR and RFA. Results. Before and after PSM, the median OS and median CSS were significantly longer in the SR group than in the RFA group ( p < 0.05 ). In the subgroup analysis, the median OS and median CSS for male and female patients with male and female patients with tumor sizes <3, 3–5, and>5 cm, age at diagnosis between 60 and 84 years, and grades I–IV tumors were longer than in the SR group than in the RFA group ( p < 0.05 ). Similar results were reported for patients who received chemotherapy ( p < 0.05 ). Univariate and multivariate analyses revealed that compared with RFA, SR was an independent favorable factor for OS and CSS ( p < 0.05 ) before and after PSM. Conclusion. Patients with SR who had a single HCC showed higher OS and CSS compared with patients who received RFA. Hence, SR should be used as a first-line treatment in cases of single HCC.