Redox factor-1 (Ref-1) is a multifunctional protein that regulates redox, DNA repair, and the response to cell stress. We previously demonstrated that Ref-1^+/− mice exhibit a significantly reduced Ref-1 mRNA and protein levels within the vasculature, which are associated with increased oxidative stress. The goal of this study was to test the hypothesis that partial loss of Ref-1 altered the cellular response to vascular injury. Fourteen days after femoral artery wire injury, we found that vessel intima-to-media ratio was significantly reduced in Ref-1^+/− mice compared with that in wild-type mice (P < 0.01). Bromodeoxyuridine labeling and transferase-mediated dUTP nick-end labeling staining at 14 days did not differ in the Ref-1^+/− mice. In vitro studies found no significant changes in either serum-induced proliferation or baseline apoptosis in Ref-1^+/− vascular smooth muscle cells. Exposure to Fas ligand; however, did result in increased susceptibility of Ref-1^+/− vascular smooth muscle cells to apoptosis (P < 0.001). Ref-1^+/− mice exhibited an increase in circulating baseline levels of IL-10, IL-1α, and VEGF compared with those in wild-type mice but a marked impairment in these pathways in response to injury. In sum, loss of a single allele of Ref-1 is sufficient to reduce intimal lesion formation and to alter circulating cytokine and growth factor expression.