Variation in the level of fetal hemoglobin (HbF) accounts for much of the clinical heterogeneity observed in patients with sickle cell disease (SCD). The HbF level has emerged as an important prognostic factor in both sickle cell pain and mortality, and a % HbF of 10-20% has been suggested as a threshold level for diminished clinical severity. The number of erythrocytes that contain HbF (termed F cells) may also be critically important, as F cells resist intravascular sickling and have preferential in vivo survival. Since F cells can be enumerated with high accuracy using flow cytometry methods, we prospectively studied a cohort of 242 children with SCD. Children with HbS and hereditary persistence of fetal hemoglobin (S/HPFH) had essentially 100% F cells. In contrast, children with homozygous sickle cell anemia (HbSS), HbS/โค 0 thalassemia, or HbS/โค ุ thalassemia had significantly lower mean % F cell values (55.9, 61.6, and 51.3%, respectively; P ฯฝ 0.001), and children with HbSC had even fewer F cells (27.0%; P ฯฝ 0.001). There was a highly significant correlation between the % F cells and the log (% HbF), which was observed for the total population of children (r โซุโฌ 0.95, P ฯฝ 0.001), as well as for each of the individual subgroups of children with HbSS (r โซุโฌ 0.94, P ฯฝ 0.001), HbSC (r โซุโฌ 0.89, P ฯฝ 0.001), or HbS/ โค 0 thalassemia and HbS/โค ุ thalassemia (r โซุโฌ 0.95, P ฯฝ0.001). This logarithmic correlation between % F cells and % HbF has not been previously described and has important implications for the pharmacologic manipulation of HbF in patients with SCD. Am.