Oncostatin-M (OSM), a hematopoietic cytokine, and vascular endothelial growth factor (VEGF), a quintessential angiogenic signal, are coexpressed in development, cancer and inflammation. Here, we report that OSM treatment of human astroglioma cell lines increases VEGF levels by approximately threefold. Interleukin-1beta (IL-1beta), in combination with OSM, induces up to sevenfold higher VEGF expression, without significantly inducing VEGF on its own. Specifically examining the OSM contribution to VEGF expression, neutralizing antibodies to OSM receptor subunits gp130 and OSMRbeta, but not LIFRbeta, inhibited OSM induction of VEGF, indicating that the OSM-specific receptor OSMRbeta/gp130 transduces the OSM signal for VEGF synthesis. OSM induction of VEGF promoter activity maps to the (-1171, -786) region of the VEGF promoter, which contains a STAT-3-binding site. STAT-3 is indeed essential for this response, since overexpression of a dominant-negative STAT-3 blocks OSM induction of VEGF promoter activity, as well as endogenous VEGF expression. Finally, we demonstrate that OSM is expressed in glioblastoma multiforme tumor biopsies, a particularly malignant form of brain tumor. This novel mechanism of VEGF regulation in astroglioma cells may be active in pathophysiological states where both OSM and IL-1beta are present.