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The purpose of this study is to investigate the prognostic value of tumor volume and radiation dose for predicting treatment outcomes in moderate-sized hepatocellular carcinoma (HCC).A total of 72 patients with unresectable HCC ranging in size from 5 to 10 cm were treated with high-dose radiotherapy including hypofractionated radiotherapy (HRT) and stereotactic body radiotherapy (SBRT), in 3 institutions from 2003 to 2013. The HRT doses ranged from 33 to 60 Gy in 3 to 10 fractions. The primary endpoint was local progression-free survival (PFS); the secondary endpoints were overall PFS, overall survival (OS), and treatment toxicity.The median follow-up period after radiotherapy was 12.8 months. The local PFS rates at 1 and 2 years were 57.0% and 39.0%, respectively, with a median of 13.6 months. The OS rates at 1 and 2 years were 70.1% and 45.2%, respectively, with a median of 21.1 months. A gross tumor volume (GTV) of 214 cm3 and a total dose of 105 Gy10 were identified as the optimal cutoff values of radiotherapeutic factors for local PFS. Patients with GTV ≤ 214 cm3 and total dose >105 Gy10 had significant higher 2-year local PFS and OS than patients with GTV >214 cm3 and total dose ≤ 105 Gy10 (P = .020 for local PFS, P = .009 for OS).The optimal cutoff values of GTV ≤ 214 cm3 and total dose >105 Gy10 may be useful for predicting survival outcomes when treating moderate-sized HCC with high-dose radiotherapy.