Inhibitors of angiogenesis, such as angiostatin, are increasingly used for targeting the tumor neovasculature and have had mixed success. Annexin II (ANX2), a 36KDa calcium and phospholipid binding protein, is a cell surface receptor for angiostatin. We hypothesized that, like normal vascular endothelium, vascular neoplasms would express ANX2, implying the potential usefulness of angiostatins in the therapy of this family of soft tissue tumors. Thirty-eight (38) vascular tumors tested included: hemangiomas - capillary [4], cavernous [6], lobular capillary [6], intramuscular hemangioma [3], spindle cell [1], and epithelioid hemangioma [4]; epithelioid hemangioendothelioma [3]; angiosarcoma [7], 4 of which were epithelioid; and angiolipomas [4]. ANX2 antibody (Zymed) was used (1/50 dilution, Ventana ES autostainer). Reactivity location (cytoplasmic, nuclear, membrane), intensity (1+/2+/3+), and quantity (focal, diffuse) was recorded. ANX2 was expressed in 97% of cases (37/38); mostly diffuse [35/37] and focal in 2 cases. Staining was strong (2+ or 3+) in 87%, and 1+ in 5/37 (14%), all benign tumors. Location was mostly cytoplasmic and membranous; no nuclear staining was seen. Both endothelium and pericytes were positive. Epithelioid angiosarcomas showed predominantly membranous staining. To our knowledge this is the first demonstration of an angiostatin receptor (ANX2) in vascular endothelial tumors including angiosarcoma. Diffuse and strong reactivity signified the absence of any down-regulation of ANX2 in both benign and malignant tumors. ANX2 reactivity may be the basis of treatment for a variety of benign tumors, especially in pediatric patients, and may offer a new and potentially less toxic therapy for angiosarcoma.