The purpose of our study was to evaluate the outcome, patterns of failure, and toxicity for patients with unresectable hepatocellular carcinoma (HCC) treated with radiotherapy, transcatheter arterial chemoembolization (TACE), or combined TACE and radiotherapy. Forty-two patients with unresectable HCC were treated with combined radiotherapy and TACE (TACE+RT group, 17 patients), radiotherapy alone (RT group, 9 patients), or with TACE alone (TACE group, 16 patients). Mean dose of radiation was 46.9 +/- 5.8 Gy in a daily fraction of 1.8 to 2 Gy, directed only to the cancer-involved areas of the liver. TACE was performed with a combination of Lipiodol, doxorubicin, cisplatin, and mitomycin C, followed by Gelfoam or Ivalon embolization. Tumor size was smaller in the TACE group (mean: 5.4 cm) compared with the TACE+RT group (8.6 cm) and the RT group (13.1 cm) (P = 0.0003). The median follow-up was 24 months in the TACE+RT group, 28 months in the RT group, and 23 months in the TACE group. Survival was significantly worse for patients treated with radiotherapy alone due to the selection bias of patients with more advanced disease and compromised condition in this group. In contrast, the TACE+RT and TACE groups had comparable survival (two-year rates: TACE+RT 58%, TACE 56%, P = 0.69). The local control rate for the treated tumors was similar in the TACE+RT and TACE groups (P = 0.11). The intrahepatic recurrence outside the treated tumors was common and similar between these two groups (P = 0.48). The extrahepatic progression-free survival was significantly shorter for patients in the TACE+RT group than in the TACE group (two-year rates: TACE+RT 36%, TACE 100%, P = 0.002). Seven patients died from complications of treatment. Local radiotherapy may be added to treat patients with unresectable HCC, and the control of progression of the treated tumors was promising even in patients with large hepatic tumors. Survival of patients with combined TACE and radiotherapy was similar to that with TACE as the only treatment, while a significant portion of the patients treated with radiotherapy developed extrahepatic metastasis.