The aim of the present study was to assess the anti-tumor effect of a defective adenovirus that expresses soluble vascular endothelial growth factor (VEGF) receptor FLT-1 (AdsFLT-1) in combination with cisplatin (cis-diamminedichloroplatinum, DDP) on human tongue carcinoma Tca8113 cell xenografts that had been pre-established in nude mice. In vitro, Tca8113 cells secreted soluble FLT-1 (sFLT-1) after infection with AdsFLT-1, and the conditioned medium from AdsFLT-1-treated Tca8113 cells seemed to inhibit VEGF-induced proliferation of human umbilical vein endothelial cells. The combined effects of sFLT-1 gene therapy and DDP chemotherapy was then studied in well-established Tca8113 xenografts. The concentration of sFLT-1 in serum reached a peak 8 days after intratumoral injection of AdsFLT-1. In these tumors, AdsFLT-1 intratumoral injections had only a small effect. Interestingly, when the cells were also exposed to DDP chemotherapy, significantly higher (P<0.05), and possibly synergistic, anti-tumoral effects were observed that were highly correlated to a marked reduction in intratumoral vascularization and an increase in tumor-cell apoptosis. Together, these data emphasize the potential of combining an anti-angiogenic gene therapy strategy with a destructive approach directed against the tumor cells to fight human tongue carcinoma.