Our recent studies (R. Pollock et al., Clin. Cancer Res., 4: 1985–1994, 1998; M. Milas et al.,Cancer Gene Ther., in press, 2000) have shown that the restoration of wild-type (wt) p53 enhances cell cycle control in vitro and inhibits the growth of human soft-tissue sarcoma in severe combined immunodeficient mice. We hypothesized that the antitumor effect of wt p53overexpression in sarcoma cells is attributable not only to enhanced cell cycle control but also to inhibition of angiogenesis. We evaluated the effect of restoring wt p53 function on angiogenesis in human soft-tissue sarcoma harboring mutant p53. Restoration of wt p53 expression in human leiomyosarcoma SKLMS-1 cells that contain mutant p53 markedly inhibited angiogenesis induced by tumor cells in vivo. Angiogenesis assays using an in vivo Matrigel plug assay demonstrated that less neovascularization in severe combined immunodeficient mice was observed with conditioned medium (CM) from human synovial sarcoma cells expressing wt p53 compared with CM from human synovial sarcoma cells expressing mutant p53. Microvessel density and microvessel counts were lower in tumor xenografts from cells containing wt p53than in tumor xenografts from cells containing mutant p53. The growth and migration of murine lung endothelial cells were decreased when cells were treated with CM from sarcoma cells expressing wt p53 compared with CM from sarcoma cells expressing mutant p53. The introduction of wt p53 into sarcoma cells containing mutant p53 significantly reduced the expression of vascular endothelial growth factor (VEGF), which is a key mediator of tumor angiogenesis. Stimulation of endothelial cell migration by CM from cells expressing mutant p53 was significantly reduced after anti-VEGF neutralizing antibody was added to the CM. Using luciferase as the reporter of VEGF promoter activity, we found that wt p53 inhibited VEGF promoter activity in SKLMS-1 cells. Deletion analysis defined an 87-bp region (bp −135 to −48) in the VEGF promoter that is necessary for inhibiting VEGF promoter activity by wt p53. The transcription factor Sp1 may be involved in the repression of VEGF promoter activity by wt p53 in SKLMS-1 cells. These data indicated that wt p53 can suppress angiogenesis in human soft-tissue sarcomas by transcriptional repression of VEGF expression.