The purpose of this study is to assess clinical efficacy and safety of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) on patients with unresectable hepatocellular carcinoma (HCC). Efficacy and safety profiles of sorafenib in combination with TACE and RFA were evaluated based on retrospective data for thirty patients with unresectable HCC. Patients were treated with TACE initially when admitted to hospital, followed by RFA 3 days after TACE. All TACE and RFA were performed by the same team of doctors. Seven days after the first TACE, patients started taking continuous sorafenib 400 mg bid without breaks until unacceptable toxicities or disease progression. The response to treatment, overall survival (OS), time to progression (TTP), and adverse effects were evaluated. The disease control rate was 33.3% by RECIST criteria. The median TTP was 15.3 months (95% CI 4.8-23.5). The median OS was 28.8 months (95% CI 12.8-39.6). At the time of data record, 13 patients (43.3%) were dead. Median OS in patients with or without portal vein thrombosis was 12.3 months (95% CI 7.6-14.5) and 30.2 months (95% CI 24.2-34.5), respectively, P = 0.018. The most common adverse events related to sorafenib were hand-foot skin reaction (53.3%) and diarrhea (33.3%). The combination of sorafenib, TACE, and RFA proved both safe and effective in the treatment for unresectable hepatocellular carcinoma patients.