Abstract: Objective To observe the efficacy and adverse effects of cyberknife (CK) versus hypofractionated (HF) three-dimensional conformal radiotherapy (3DCRT) for patients with hepatocellular carcinoma (HCC). Methods In this retrospective study, clinical data about 69 patients (CK group: n=30, 3DCRT group: n=39) with hepatocellular carcinoma who were treated by cyberknife or hypofractionated three-dimensional conformal radiotherapy in department of radiation oncology, Jinan Military General Hospital from June 2013 to June 2015 were analyzed. Baseline data of patients in the two groups were comparable. Patients in CK group received total dose of 36-50 Gy/2-5f, 1 fraction/day, while patients in 3DCRT group at a total dose of 31.5-66 Gy/7-19f, 1 fraction/day or once every other day. Results The follow-up time was 6 to 30 months with the follow up rate of 95.65%. The short-term objective response rates in CK group and 3DCRT group were 73.33% vs 64.10% (P=0.606), the 1-year overall survival rates were 70.84% vs 56.67% (P=0.473) and the rate of side effect were 16.67% vs 41.03% (P=0.029). The number of liver function deterioration cases was 2 vs 9, and the radiationinduced liver disease was 0 vs 2. Conclusion Compared with the treatment of hypofractionated three-dimensional conformal radiotherapy, cyberknife has low side effect rate for patients with hepatocellular carcinoma, while the local control and survival advantage are not obvious.