Redox factor 1 (Ref-1) is a multi-functional protein that regulates redox, DNA repair and the response to cell stress. We previously demonstrated that Ref-1 (+/-) mice exhibit a significant reduced Ref-1 mRNA and protein levels within the vasculature, which is 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 /media ratio was significantly reduced in Ref-1 (+/-) mice compared to wild type (WT) (p<0.01). BrdU labeling and TUNEL 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 (VSMC). Exposure to Fas ligand; however, did result in increased susceptibility of Ref-1 (+/-) VSMCs to apoptosis (p < 0.001). Ref-1 (+/-) mice exhibited an increase in circulating baseline levels of IL-10, IL-1 and VEGF compared to WT, 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 alter circulating cytokine and growth factor expression.