Human urotensin-II (hU-II) is a vasoactive peptide associated with remodeling processes in many cardiovascular diseases. However, the signaling mechanisms activated by this peptide are not well understood. In endothelial cells, NADPH oxidases are important sources of ROS known to act as signaling molecules in angiogenic processes. We investigated whether hU-II plays a role in regulating ROS production and angiogenesis in HUVEC. HUVEC expressed the NADPH oxidase homologues NOX2 and NOX4. Overexpression of NOX2 or NOX4 increased endothelial ROS production. Stimulation with 100 nM hU-II elevated NOX2 and NOX4 proteins in a time-dependent manner and increased ROS generation. Treatment with hU-II for 24 hours or overexpression of NOX2 or NOX4 enhanced formation of capillary-like structures in an in vitro angiogenesis assay. Application of antioxidants or depletion of NOX2 or NOX4 by specific siRNA diminished not only hU-II-stimulated ROS production, but also angiogenesis. These results show that hU-II is a potent activator of angiogenesis in HUVEC. This response was redox-sensitive and allowed by upregulation of NOX2 and NOX4. Since sustained elevation of ROS and angiogenesis are observed in vascular remodeling processes, this pathway may thus provide a novel mechanism how hU-II contributes to these pathologies.