Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide, and novel therapeutic strategies are urgently required to improve clinical outcome. Interferon-alpha (IFN-alpha) and sorafenib are widely used as anti-tumor agents against various malignancies. In this study, we investigated the combined effects of IFN-alpha and sorafenib against HCC. We demonstrated that the combination therapy synergistically suppressed HCC cellular viability; arrested cell cycle propagation and induced apoptosis in HCC cells. Further research revealed that IFN-alpha and sorafenib collaboratively regulated the expression levels of cell cycle-related proteins Cyclin A and Cyclin B as well as the pro-survival Bcl-2 family proteins Mcl-1, Bcl-2 and Bcl-X-L. Moreover, sorafenib inhibited IFN-alpha induced oncogenic signaling of STAT3, AKT and ERK but not the activation of the tumor suppressor STAT1. Xenograft experiments also confirmed the combined effects of IFN-alpha and sorafenib on tumor growth inhibition and apoptosis induction in vivo. In conclusion, these results provide rationale for the clinical application of IFN-alpha and sorafenib combination therapy in HCC treatment. (C) 2012 Elsevier Inc. All rights reserved.