Persistent inflammation and neovascularization are critical to cancer development. In addition to upregulation of positive control mechanisms such as overexpression of angiogenic and inflammatory factors in the cancer microenvironment, loss of otherwise normally functioning negative control mechanisms is likely to be an important attribute. Insights into the down-modulation of such negative control mechanisms remain largely unclear, however. We show here that tumor necrosis factor superfamily-15 (TNFSF15), an endogenous inhibitor of neovascularization, is a critical component of the negative control mechanism that operates in normal ovary but is missing in ovarian cancer. We show in clinical settings that TNFSF15 is present prominently in the vasculature of normal ovary but diminishes in ovarian cancer as the disease progresses. Vascular endothelial growth factor (VEGF) produced by cancer cells and monocyte chemotactic protein-1 (MCP-1) produced mainly by tumor-infiltrating macrophages and regulatory T cells effectively inhibits TNFSF15 production by endothelial cells in vitro. Using a mouse syngeneic tumor model, we demonstrate that silencing TNFSF15 by topical shRNA treatments prior to and following mouse ovarian cancer ID8 cell inoculation greatly facilitates angiogenesis and tumor growth, whereas systemic application of recombinant TNFSF15 inhibits angiogenesis and tumor growth. Our findings indicate that downregulation of TNFSF15 by cancer cells and tumor infiltrating macrophages and lymphocytes is a pre-requisite for tumor neovascularization.