When the clinical manifestations of 272 patients with sickle cell anemia are compared with their level of fetal hemoglobin (HbF), the results suggest that there may be a threshold above which HbF is effective in ameliorating the morbidity of this disease. The age of entry of these SS patients into the study ranged from birth to 56 yr; the average length of follow-up was 11 yr for a total of 3,011 patient- years of clinic observation. HbF was determined quantitatively by microchromatographic procedures; the mean for HbF was 10% +/- 6% with a range from 2% to 32%. For major organ failure, analyzed as termination events of morbidity, such as stroke or aseptic necrosis, the threshold appears to be 10%, whereas for recurrent clinical events, such as crisis or pulmonary disorders, it is 20%. No linear trend was found between HbF levels and morbidity. If a threshold exists, it is important to recognize this fact when attempts are made to raise the level of HbF in patients with sickle cell disease.