To investigate the feasibility and efficacy of liver gene therapy mediated by intrasplenic transplantation of genetically modified hepatocytes, the normal mouse liver cell line BNL CL. 2 cells were introduced with Neo-resistant (NeoR) gene or interleukin-2 (IL-2) genein vitro, and transplanted intrasplenically into normal syngeneic mice (2 x 10(6) cell/mouse); subsequently, the expressions of the introduced genesin vim were detected. The RT-PCR results showed that NeoR mRNA expressions were detectable in livers 24 h after transplantation and lasted over 11 weeks. Moreover, The NeoR mRNA was detected to be expressed temporarily in spleens (24 h-1 week) and lungs (24-96 h) after transplantation. After intrasplenic transplantation of IL-2 gene-modified BNL CL.2 cells, the stable expressions of IL-2 mRNA in the livers of transplanted mice were detectable by RT-PCR (24 h-11 weeks), and certain levels of IL-2 (5-40 pg/mL) remained in the peripheral blood. When IL-2 gene-modified BNL CL. 2 cells were transplanted intrasplenically to treat the metastatic liver colon carcinoma-bearing mice, the survival time of the treated mice was significantly prolonged. The data indicate that intrasplenic transplantation of genetically modified hepatocytes could allow for oriental distribution in host livers and long-term survival of the transplanted liver cells, and effective expression of exogenous genesin vim, suggesting that this can be a candidate approach to liver-directed gene therapy.