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Background: Liver resection (LR) is considered the main therapeutic strategy for small hepatocellular carcinomas (HCCs) (<3 cm). Recently, the efficacy of complete response after radiofrequency ablation (RFA) in medium-sized HCCs (3–5 cm) has been proposed. Comparative analyses of LR and RFA in HCC patients with single or multiple nodules and tumor sizes ranging from 3 to 5 cm are lacking. Aim: The purpose of this study is to compare the long-term outcomes of 132 patients diagnosed with medium-sized HCCs between 2010 and 2017 who underwent LR (n = 72) or RFA (n = 60) and met the inclusion criteria. Methods: Data were retrospectively analyzed using a prospective database. The treatment-related outcomes and risk factors of overall survival (OS) and disease-free survival (DFS) were investigated using univariate and multivariate Cox regression analyses. Results: The hospital stay was shorter in the RFA group than in the LR group (5.4 days vs. 14.3 days, respectively; P < 0.0001). RFA was associated with fewer treatment-related complications. OS and DFS were better in the LR group than in the RFA group. Treatment modality and albumin and alpha-fetoprotein levels were predictors for OS, while treatment modality and tumor number were predictors for DFS. Conclusion: LR is an effective treatment for patients with medium-sized HCCs in terms of long-term outcomes (OS and DFS), while RFA may be used as an alternative treatment to LR with comparable OS.