We determined the role that vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), plays in the progression of human renal cell cancer in nude mice. Low metastatic and low VEGF/VPF-expressing human renal cancer cells SN12C were transfected with the VEGF165 cDNA or plasmid alone as control. VEGF165-transfected SN12C cells produced large amounts of biologically active VEGF in culture that did not affect cell doubling time or confluence. Subsequent to implantation into the renal subcapsule of nude mice, the VEGF165-transfected SN12C cells produced fast-growing (PCNA labeling), large tumors that expressed high levels of VEGF/VPF and were well vascularized (CD3-positive vessels). The tumors produced hyperpermeability of peritoneal blood vessels (Evans blue dye-leak assay), bloody ascites, and short survival time. Parental or control transfected SN12C cells produced less vascularized, slower growing tumors with no ascites. Regardless of in vivo expression level of VEGF, the incidence of spontaneous lung metastasis was low, suggesting that in itself, the expression of VEGF/VPF by renal cancer cells is not sufficient to produce metastasis.