Receptor-mediated gene delivery is an attractive method for gene transfer in vitro and shows promise for in vivo gene therapy applications. In the current study, we have selected the cytokine interleukin-2 (IL-2) gene to explore the feasibility of receptor-mediated gene transfer into human hepatocellular carcinoma HepG2 cells, using Epstein-Barr virus (EBV)-based vectors. We have developed a targeted DNA delivery system for the treatment of liver cancer by gene therapy. This system utilizes the hepatocyte-specific asialoglycoprotein receptor, which is uniquely expressed on liver cell membranes but not present on other cell types. Galactosylated histone, a ligand to the asialoglycoprotein receptors, was synthesized, and a new EBV-based expression vector bearing the human IL-2 cDNA was constructed and conjugated to the ligand through ionic interactions. The ligand/IL-2 DNA complex was able to bind specifically to cell-surface receptors on the target cell and, when incubated with HepG2 cells, resulted in elevated levels of IL-2 gene expression. These results indicate that therapeutic genes like IL-2 in ligand/DNA complex can be transferred into hepatoma cells via the hepatocyte receptor. This study constitutes an encouraging first step in the assessment of receptor-mediated gene transfer as a technique for gene therapy in liver cancer.