Adult and embryonic stem cells hold great promise for regenerative medicine. Expression profiling of stem cells revealed a characteristic imprint of genes, so-called “stemness” genes, providing resistance to stress. Circulating progenitor cells with an endothelial phenotype (EPCs) can be isolated from peripheral blood and contribute to neovascularization and endothelial regeneration. We investigated whether EPCs are equipped with an antioxidative defense to provide resistance against oxidative stress. EPCs exhibited a significantly lower basal reactive oxygen species (ROS) concentration as compared with mature umbilical vein endothelial cells (HUVECs). Incubation with H₂O₂ (500 μM) or the redox cycler LY-83583 (10 μM) profoundly increased the ROS concentration to 3- and 4-fold and induced apoptosis in HUVECs. In contrast, H₂O₂ and LY-83583 induced only a minor increase in intracellular ROS levels and apoptosis in EPCs. Consistently, the expression of the intracellular antioxidative enzymes catalase, glutathione peroxidase and manganese superoxide dismutase (MnSOD), was significantly higher in EPCs versus HUVECs and human microvascular endothelial cells. In accordance, combined inhibition of these antioxidative enzymes increased ROS levels in EPCs and impaired EPC survival and migration. Taken together, EPCs reveal a higher expression of antioxidative enzymes and, thus, are exquisitely equipped to be protected against oxidative stress consistent with their progenitor cell character.