Variation in the level of fetal hemoglobin (HbF) accounts for much of the clinical heteroge-neity 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/ 0 thalassemia, or HbS/ thalassemia had significantly lower mean % F cell values (55.9, 61.6, and 51.3%, respectively; P 0.001), and children with HbSC had even fewer F cells (27.0%; P 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 0.95, P 0.001), as well as for each of the individual subgroups of children with HbSS (r 0.94, P 0.001), HbSC (r 0.89, P 0.001), or HbS/ 0 thalassemia and HbS/ thalassemia (r 0.95, P 0.001). 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.