Giant hemangiomas of infancy remain a difficult clinical problem, responding in only about 30% of cases to conventional therapies. In such lesions, as in the normal processes of development, vessel formation is modulated by both angiogenic and anti-angiogenic factors. We have identified a novel mediator, Endothelial-Monocyte Activating Peptide (EMAP) II, which has striking anti-angiogenic properties. It acts in part by inducing apoptosis(programmed cell death) in growing endothelium, a property which may have special relevance to the clinical problem of hemangioma in infants. We studied the effect of EMAP II in a murine model of developing hemangioma, measuring a) tumor volume b) histologic changes and c) hematologic effects.Methods: Py-4-1 cells are derived from transgenic mice who develop lethal hemangiomas. Development of these lesions is associated with hematologic changes resembling those found in the Kasabach-Merritt syndrome in humans, including consumptive coagulopathy. After implantation of 1 × 106 cells in histocompatible mice, local tumors formed within 3 days. EMAP II was administered intraperitoneally to subject mice at doses of 1 and 10 mcg each 12h for 15 days. Tunor volume using a spherical model was measured every 72h. Tumor sections were fixed and stained with H & E. Blood was obtained for platelet counts and peripheral smear examination. Main Results: Injection of Py-4-1 cells resulted in hemangioma formation in 100% of animals by 3 days. Control mice formed giant hemangiomas, resulting in death of 40% by day 15. In contrast, EMAP II-treated animals were all alive and healthy. The administration of EMAP II resulted in a) smaller tumor volumes (P <0.02) in a dose-dependent manner b) decreased vascularity and diminished stroma histologically and c) significantly suppressed manifestations of consumptive coagulopathy (thrombocytopenia, microangiopathic changes on peripheral smear). Conclusion: Administration of EMAP II inhibited the development of giant hemangiomas in a murine model. Both tumor growth and neovessel development were suppressed. The hematologic manifestations associated with hemangioma were significantly ameliorated. The potent suppression of hemangioma formation by EMAP II appears to correspond to its action on growing endothelium, and has not been previously described.