In angiogenesis, new blood vessels are generated from pre-existing ones. It plays a major role in tumor growth and metastasis. The main pro-angiogenic factor is the vascular endothelial growth factor (VEGF). VEGF displays high specificity for vascular endothelial cells and also elicits a pronounced angiogenic response in a variety of in vivo models. VEGF withdrawal has been shown to result in regression of vasculature in tumors. The pathogenic and the angiogenic processes of Langerhans cell histiocytosis (LCH) are not yet clear. The purpose of this study was to investigate the extent of the angiogenic response in LCH tumors. The authors examined tissue sections from LCH patients with single lesion (5 patients) or multisystem disease (5 patients). The preparations were examined by using monoclonal anti-VEGF antibody, CD34, and factor VIII-like antigen. VEGF was expressed in 70% of the cases examined. All the multisystem lesions were positive, as were two of the five single-lesion tumors. LCH cells expressed VEGF. The blood vessel density was significantly higher within the lesion than in normal margins. The findings that VEGF was expressed in LCH cells and that all multisystem lesions were VEGF producers raise the possibility of using anti-angiogenic drugs to treat these patients. Further studies to explore the role of angiogenesis in LCH are warranted.