Chronic inflammation is a salient feature of sickle cell disease (SCD) and transgenic-knockout sickle (BERK) mice. Inflammation is implicated in the activation of hypoxia-inducible factor-1α (HIF-1α) under normoxic conditions. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1α, a transcription factor with wide-ranging effects including activation of genes for vasoactive molecules. To this end, we have examined the expression of HIF-1α in normoxic BERK mice expressing exclusively human α- and β(S)- globins, and evaluated the effect of fetal hemoglobin (HbF) in BERK mice (i.e., <1.0%, 20%, and 40% HbF). HbF exerts antisickling and anti-inflammatory effects. Here, we show that HIF-1α is expressed in BERK mice under normoxic conditions, accompanied by increased expression of its vasoactive biomarkers such as VEGF, heme oxygenase-1 (HO-1), and serum ET-1 levels. In BERK mice expressing HbF, HIF-1α expression decreases concomitantly with increasing HbF, commensurately with increased NO bioavailability, and shows a strong inverse correlation with plasma NO metabolites (NOx) levels. Reduced HIF-1α expression is associated with decreased HO-1, VEGF, and ET-1. Notably, arteriolar dilation, enhanced volumetric blood flow, and low blood pressure in normoxic BERK mice all show a trend toward normalization with the introduction of HbF. Also, arginine treatment reduced HIF-1α, as well as VEGF expression in normoxic BERK mice, supporting a role of NO bioavailability in HIF-1α activation. Thus HIF-1α expression in normoxic sickle mice is likely a consequence of chronic inflammation, and HbF exerts an ameliorating effect by decreasing sickling, increasing NO bioavailability, and reducing inflammation.