Background: Invasion of major hepatic vessels in hepatocellular carcinoma (HCC) generally prohibits the surgical treatment. Objective: Analyze outcomes of non-surgical approaches in this group of HCC. Methods: Retrospective review of medical records of 648 HCC admitted to King Chulalongkorn Memorial Hospital between January 2003 and December 2005 was carried out to select only patients who had unresectable HCC with vascular invasion and hepatic functions-Child-Pugh class-A. Vascular invasion was defined as involvement of portal vein, inferior vena cava (IVC), or their branches identified by imaging techniques. Non-surgical treatments were either transarterial chemoembolization (TACE) or systemic chemotherapy (SCT) in addition to general supportive care. Treatment outcomes of the patients were analyzed. Results: Out of 71 unresectable HCC patients enrolled, 57patients were treated with TACE, while 14 received SCT. In the TACE group, 39 (68%), 7 (12%) and 11 (19%) patients had portal vein, IVC, and both vessels invasion, respectively. In the SCT group; 11 (78%), 1 (7%) and 2 (14%) had invasion of portal vein, IVC, and both vessels, respectively. Median overall survival in both groups was 158 days. Univariate analysis demonstrated that AFP level <1000 ng/mL, tumor size <10 cm, and SCT treatment significantly influenced survival. Additional multivariate analysis confirmed that diameters of tumor, and SCT were independent prognostic factors for good survival. A survival analysis showed longer survival in the SCT group than that of TACE (210 vs. 149 days, p=0.03) group. Conclusion: Survival of HCC patients with major vessels invasion was better when treated with SCT compared to TACE. Future prospective study in larger populations to test the hypothesis is warranted.