BACKGROUND The Barcelona Clinic Liver Cancer (BCLC) staging system for hepatocellular carcinoma (HCC) recommends transarterial chemoembolization (TACE) as the first line therapy for stage B patients and sorafenib treatment for stage C patients. However, stage C patients exhibit variations in terms of tumor burden, liver function, and extrahepatic metastasis, which could potentially affect disease outcome. Here, we assessed whether the Cancer of the Liver Italian Program (CLIP) scores can help identify stage C patients likely to benefit from TACE. METHODS Out of 295 BCLC stage C HCC patients enrolled between January 2009 and December 2011, those with platelet counts >30 X 10(9) cells/L, total bilirubin <51 μmoL/L, and an unobstructed main portal vein were scheduled for TACE (n=195). The remaining patients received best supportive care (BSC, n=100). All the patients were followed up for symptoms, performance status, and Child-Pugh classification scores every 4 weeks until death or December 2013. The prognosis of each group was evaluated by using the log-rank test and Cox-Mantel test. RESULTS The median overall survival (OS) was 6 months [95% confidence interval (CI): 4.64-7.36]. The OS was 9 months for the TACE group and 4 months for the BSC group. The TACE group had a longer OS than the BSC subgroup for CLIP scores 0-2 [13 months (95% CI: 8.55-17.45) vs 4 months (95% CI: 0.00-10.96), P=0.001]. No significant differences were found between the TACE and BSC groups for CLIP scores 3-5. The CLIP score and treatment methods were found to be independent prognostic factors. CONCLUSIONS BCLC stage C HCC patients exhibit definite disease heterogeneity and can be reclassified by using the CLIP scoring system. Moreover, patients with CLIP scores 0-2 are likely to benefit from TACE. However, additional studies with long-term follow-up will be required to validate these findings.