Several studies have examined the expression profiles of human hepatocellular carcinomas (HCCs) using high density microarray technology, but subtyping with potential mechanistic and therapeutic impact has not been achieved so far. Here we have analysed the expression pattern of human HCCs and HCC cell lines in comparison to normal liver. A characteristic of one group of HCCs and all HCC cell lines was overexpression of insulin-like growth factor (IGF)-II. Moreover, IGF-II expression was mutually exclusive to induction of several IFN-related genes. In vitro, treatment of HCC cells with IFNgamma leads to a strong reduction of IGF-II expression. Equally, specific reduction of IGF-II was achieved using RNAinterference in HCC cells. Therefore, IGF-II may represent an excellent target for IFNgamma-treatment and specific siRNA-mediated therapeutic intervention.