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Liver cancer is one of the most common malignant cancers worldwide. Systemic chemotherapy remains the major treatment option, but with severe adverse effects. Combinations of systemic with targeted treatments may provide effective therapeutics. The objectives of this study were to demonstrate if insulin-like growth factor-I receptor (IGF-IR) might serve as a functional target for liver cancer treatment and to investigate the chemo-sensitizing activity of IGF-IR downregulation. IGF-IR knockdown was achieved by stable transfection of liver cancer cells with IGF-IR small interfering RNA (siRNA). IGF-IR knockdown resulted in reduced growth, clonogenic survival, adhesion and migration of liver cancer cells, and increased sensitivities of liver cancer cells to apoptosis-inducing agents and chemotherapeutic drugs in vitro. In the animal studies, both IGF-IR knockdown and adriamycin (ADM) treatment significantly reduced the growth of liver tumors. IGF-IR knockdown enhanced the effect of ADM on tumor growth by further reducing tumor angiogenesis and inducing tumor cell apoptosis. The final tumor sizes in the IGFIR-siRNA, ADM-treated EGFP, and ADM-treated IGFIR-siRNA groups were significantly reduced by 52.5%, 33.8%, and 86.3%, respectively, compared with that in the EGFP control, suggesting that the ADM and the IGF-IR knockdown inhibit the growth of liver tumors in a synergistic manner. These results support that IGF-IR may serve as a functional molecular target for liver cancer treatment, and that the combination of systemic chemotherapy with targeted IGF-IR suppression may provide an effective treatment strategy for liver cancer.