BACKGROUND AND AIM: The clinical utility of alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) as a predictor of treatment outcome in patients with advanced hepatocellular carcinoma (HCC) receiving hepatic artery infusional chemotherapy (HAIC) or concurrent chemoradiation therapy (CCRT) has been poorly defined. METHODS: Between January 2003 and December 2007, we enrolled 127 treatment-naïve patients who received HAIC (n = 60) or CCRT (n = 67) as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 20% from the baseline level. RESULTS: AFP responders showed significantly better overall survival (OS) than non-responders among patients with HAIC (median 17.3 vs 6.4 months, P < 0.001) and with CCRT (median 17.6 vs 8.7 months, P = 0.014). DCP responders in the CCRT group also showed significantly better progression-free survival (PFS) than non-responders (median 9.2 vs 3.1 months, P < 0.001). Multivariate Cox regression analyses showed that AFP response was independently predictive of OS in both groups (P = 0.009 in HAIC and P = 0.008 in CCRT) whereas DCP only predicted PFS in patients with CCRT (P = 0.015). CONCLUSIONS: Early on-treatment AFP response was predictive of OS in treatment-naïve patients with advanced HCC receiving HAIC and CCRT as an initial treatment modality. Furthermore, DCP response was useful for predicting PFS in patients with CCRT.