Melanoma tumor growth and progression are highly dependent on adequate blood supply through angiogenesis. Since several genes involved in angiogenesis revealed potential binding sites for the transcription factor Sp1, we have examined the effects of local inoculation of Sp1 decoy oligodeoxynucleotides (ODNs) on the growth of transplanted murine melanoma tumors and the expression of VEGF and TNF-α within these tumors. Treatment with Sp1 decoy ODNs, but not their mutated form, led to a significant increase (P=0.041) of the tumor necrotic area, as evaluated morphometrically. Tumor necrosis was associated with a significant decrease of microvascular density (P=0.012) and relative vascular area (P=0.026), as determined by counting CD34-positive vascular structures within the tumor microenvironment of Sp1 decoy ODNs and control ODN-treated tumors. RT-PCR experiments showed a strong decrease in the levels of VEGF188 and VEGF164 isoforms and a moderate decrease of TNF-α in Sp1 decoy-treated tumors. Taken together, our results indicate that Sp1 decoy ODNs may inhibit angiogenesis by affecting the gene expression of key players in angiogenesis such as TNF-α and VEGF. These findings indicate that Sp1 decoy ODNs may be a potential new therapeutic tool in antiangiogenic therapy.