Abstract Leg ulcerations have long been identified as a serious and debilitating complication of sickle cell disease (SCD).The first SCD patient described in North America in 1910 had leg ulcerations. Prevalence varies, being low before 10 years of age and in genotypes other than SS. It is influenced by geographical location, with occurrence as high as 75% in SS patients in Jamaica, and 8-10% in North America. The etiology of chronic ulcers in SCD and other hemolytic disorders is unknown - mechanical obstruction by dense sickled red cells, increased venous pressure, bacterial infections, abnormal autonomic control with excessive vasoconstriction when in dependent position, degree of anemia with decrease in oxygen carrying capacity, have all been proposed as potential contributing factors. Morbidity from chronic leg ulcers remains a substantial clinical burden in patients with SCD despite advances in care with disease-modifying agents such as hydroxyurea, blood transfusions, and improved supportive care. Patients with sickle cell disease and leg ulcers have biomarkers of more severe hemolytic anemia, a state associated with low bioavailability of nitric oxide. Existing therapeutic approaches for SCD ulcers are unsatisfactory, and are mostly based on treatments for venous and arterial ulcers in the general population. A recent Cochrane review identified only six prospective, randomized therapeutic trials for sickle cell disease leg ulcers over the past 30 years—four in Jamaica and two in the USA. Results were mixed; statistically significant increases in wound closure were reported only for topical Arg-Gly-Asp (RGD) peptide and intravenous arginine butyrate. As these agents remain in early-phase drug development, patients have few therapeutic options available. We selected sodium nitrite for clinical development on the basis of the extensive published literature about its safety profile when administered intravenously and orally, its vasodilating properties, and preliminary reports of the efficacy of acidified nitrite in the treatment of other patient populations with chronic skin ulcers. In animals, sodium nitrite therapy promotes revascularization of ischemic limbs, protects against ischemic infarction of the heart, liver, and brain, and has a protective effect against cardiac arrest-mediated heart and brain injury. The nitrite anion acts as a vasodilator in vivo by generating nitric oxide in tissues with low oxygen tension and pH, conditions which are likely to be present in chronic wounds. The mechanism involves oxygen- dependent and pH-dependent nitrite reductase activity of hemoproteins or xanthine oxidoreductase. Experimental models suggest beneficial effects of nitric oxide in the early and late phases of wound healing, including increased extracellular matrix production, immune response modulation, and stimulation of keratinocyte cell proliferation, angiogenesis, and bactericidal properties. Nitric oxide mediates essential vascular homoeos...