Objective:To compare the clinical efficacy of liver resection (LR) and radiofrequency ablation (RFA) in the treatment of peripheral single small hepatocellular carcinoma.Methods:Clinical data of 219 patients with peripheral single small hepatocellular carcinoma admitted to Beijing You'an Hospital Affiliated to Capital Medical University from January 2015 to December 2018 were retrospectively analyzed. Among them, 169 patients were male and 50 female, aged from 34 to 76 years, with a median age of55 years. The tumor diameter was ≤4 cm. 121 patients underwent liver resection (LR group) and 98 patients received RFA treatment (RFA group). The informed consents of all patients were obtained and the local ethical committee approval was received. All patients were subject to 1:1 propensity score matching (PSM). Postoperative intrahepatic recurrence, extrahepatic recurrence, progression-free survival (PFS) and overall survival (OS) after PSM were analyzed between two groups. Survival analysis was performed by Kaplan-Meier curve and Log-rank test.Results:After PSM, 60 patients were assigned into each group. In the LR group, the postoperative 1-, 3-, 5- and 7-year PFS rates were 93.7%, 69.0%, 58.0% and 53.8%, significantly better compared with 89.2%, 45.4%, 30.1% and 14.1% in the RFA group (HR=1.09, P<0.05). The postoperative 1-, 3-, 5- and 7-year OS rates in the LR group were 99.4%, 90.5%, 89.4% and 87.9%, significantly better than 98.9%, 89.3%, 79.1% and 74.1% in the RFA group (HR=1.35, P<0.05). The postoperative 1-, 3-, 5- and 7-year cumulative intrahepatic recurrence rates in the LR group were 5.0%, 20.1%, 32.6% and 40.1%, and 12.9%, 40.3%, 70.3% and 78.7% in the RFA group, and significant differences were observed (HR=3.16, P<0.05). The postoperative 1-, 3-, 5- and 7-year cumulative extrahepatic recurrence rates in the LR group were 1.2%, 4.4%, 7.8% and 10.5%, and 1.6%, 6.6%, 13.5% and 16.9% in the RFA group, and no significant differences were observed (HR=0.47, P>0.05). Subgroup analysis showed that intrahepatic and extrahepatic recurrence, PFS and OS rates of periportal vein hepatocellular carcinoma patients in the LR group were significantly better than those in the RFA group (HR=0.24, 0.68, 0.25, 0.22; P<0.05). However, only intrahepatic recurrence rate of patients with peripheral hepatocellular carcinoma of hepatic vein in the LR group was better than that in the RFA group (HR=0.16, P<0.05).Conclusions:For peripheral single small hepatocellular carcinoma, liver resection yields better long-term tumor control and OS compared with RFA, especially for patients with periportal vein hepatocellular carcinoma. Liver resection should be delivered if patients are eligible for surgical indications.