Hepatocyte growth factor (HGF) promotes angiogenesis and prevents senescence of endothelial cells. Reactive oxygen species (ROS) play an essential role in angiogenesis. One of the most important sources of acutely induced ROS-production are the members of the NADPH oxidase (Nox) family, in endothelial cells namely Nox2. The angiogenetic potential induced by HGF depends on Nox2. The ability of HGF to induce aortic ring outgrowth was significantly reduced in aortic rigs of Nox2 deficient (Nox2y/- ) mice when compared to wildtype mice. Mobilization of endothelial progenitor cells (EPCs) from the bone marrow into peripheral blood has been suggested to be an essential step in the formation of new vessels. Indeed HGF induced mobilization of EPCs in wildtype mice. This effect of HGF was blocked in Nox2y/- mice. Accordingly in wildtype mice HGF induced colony forming unit formation which was absent in Nox2y/- mice. In human EPCs HGF acutely induced the production of hydrogen peroxide measured by Amplex Red. After depletion of Nox2-expression by antisense-oligonucleotides no HGF inducible ROS production was detectable. Further analyses revealed an HGF inducible phosphorylation of Jak2 and STAT3 which was absent in Nox2 depleted cells. We conclude that EPC mobilization might contribute to the angiogenetic effects of HGF. Nox2 derived ROS play an essential role in HGF inducible EPC-mobilization and aortic ring outgrowth.