The growth of solid tumors is dependent on angiogenesis, the formation of new blood vessels. Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific growth factor, which is induced by tissue hypoxia and is angiogenic in vivo. We investigated VEGF expression in squamous cell head and neck carcinomas by immunohistochemical techniques. All of the 156 patients studied had been treated with radical surgery and postoperative radiotherapy and were followed up until death or for at least 5 years. Of the tumors examined, 31% showed cytoplasmic staining for VEGF in carcinoma cells. Some of the tumor-infiltrating inflammatory cells, including plasma cells and tissue macrophages, showed high levels of VEGF expression in all of the carcinomas studied. Staining for VEGF was also found in acinic epithelial cells of histologically normal salivary glands and in normal stratified squamous epithelium adjacent to tumor. No association was observed between the VEGF expression of carcinoma cells and histologic grade, TNM stage, tumor microvessel count, or overall survival. These results demonstrate that in squamous cell head and neck cancer, in addition to being expressed by cancer cells VEGF is frequently expressed by tumor infiltrating inflammatory cells and by cells of histologically normal adjacent tissues; this suggests a possible role in tumor angiogenesis. Our results also suggest that angiogenic factors other than VEGF might provide the positive regulatory signals needed for tumor angiogenesis. In squamous cell head and neck cancer, carcinoma cell VEGF expression is not a prognostic marker.