VEGF165 is necessary to the metastatic potential of Fas(-) osteosarcoma cells but will not rescue the Fas(+) cells. Our previous studies showed that Fas expression correlates inversely with the metastatic potential of osteosarcoma (OS) cells and that the manipulation of Fas expression alters the lung metastatic phenotype. However, the role of VEGF in the growth and metastases of OS is unclear. The purpose of this study was to determine whether altering VEGF expression affects lung metastatic potential. LM7 metastatic OS cells were transfected with a small interfering RNA targeting human VEGF165 (LM7/siVEGF165) or a pcDNA4 plasmid expressing human VEGF165 (LM7/VEGF). We confirmed that VEGF165 expression was decreased in LM7/siVEGF165 cells and was increased in LM7/VEGF clones compared with control transfected clones. Fas expression was not altered in these transfected clones. We also transfected LM7 cells with Fas (LM7/Fas) or Fas together with VEGF165 (LM7/Fas/VEGF) to determine whether the overexpression of VEGF165 could enhance the metastatic potential of LM7 OS cells with high Fas expression (Fas(+)). LM7/siVEGF165 and LM7/Fas cells showed decreased lung metastatic potential. In addition, the overexpression of VEGF had no effect on the ability of LM7/Fas cells to form lung metastases. We therefore concluded that VEGF165 is critical to lung metastatic potential but is not sufficient to allow Fas(+) OS cells to survive in the Fas ligand lung microenvironment.