Hemangioendotheliomas are classified as endothelial cell tumors, which are the most common soft tissue tumors in infants. In a murine model of hemangioendothelioma, we previously showed that MCP-1 is required for its development and that the expression of MCP-1 in EOMA cells is redox sensitive. Here, we sought to identify the source of oxidants that drive hemangioendothelioma formation. Seven known isoforms exist of the catalytic subunit gp91. Only the nox-4 isoform of gp91 was present in EOMA cells, in contrast with non-tumor-forming murine endothelial cells that contained multiple forms of nox. Nox-4 knockdown markedly attenuated MCP-1 expression and hemangioendothelioma formation. We report that in EOMA cells, nox-4 is localized such that it delivers H2O2 to the nuclear compartment. Such delivery of H2O2 causes oxidative modification of DNA, which can be detected in the urine of tumor-bearing mice as 8-hydroxy-2-deoxyguanosine. Iron chelation by in vivo administration of deferoxamine improved tumor outcomes. The current state of information connects nox-4 to MCP-1 to form a major axis of control that regulates the fate of hemangioendothelioma development in vivo.