Significance Glutathione (GSH)-protein adducts are oxidative posttranslational modifications that are reversed by glutaredoxin-1 (Glrx). We show that ischemia-induced oxidants promote revascularization through GSH adducts on hypoxia-inducible factor (HIF)-1α, an angiogenic transcriptional factor. GSH adducts on Cys ⁵²⁰ stabilize HIF-1α protein, and depletion of Glrx stabilizes HIF-1α in vitro and increases angiogenic gene expression. Glrx ablation in vivo increases GSH adducts in ischemic muscles after femoral artery ligation in mice and improves blood flow recovery associated with increased HIF-1α and VEGF expression. Thus, increased GSH-protein adducts on HIF-1α in ischemic limbs are beneficial in promoting angiogenesis. Our data indicate HIF-1α is a novel in vivo target of Glrx, and inhibition of Glrx is a potential therapeutic strategy to improve ischemic limb revascularization.