The hematology and pathophysiology of sickle cell disease during the postnatal development of younger hemoglobin (Hb) S homozygotes (SS) could be considerably affected by a variability of alpha globin gene numbers. We have documented longitudinal developmental changes of hematological values and hemoglobin composition on 147 patients with SS (alpha alpha/alpha alpha), 64 with SS (-alpha/alpha alpha), and 9 with SS (-alpha/-alpha) between the ages of 1 and 15 years. Non-steady-state data were excluded from these analyses. The number and organization of alpha globin genes was established by gene mapping. As anticipated, mean corpuscular volume and erythrocyte counts correlated with alpha globin gene numbers throughout the 15-year age interval. On the other hand, SS children with alpha alpha/alpha alpha, -alpha/alpha alpha, -alpha/-alpha had similar hemoglobin concentrations up to the ages of 5-10 years. Around the age of 7, the SS patients with -alpha/-alpha developed a higher Hb concentration than that of the SS (-alpha/alpha alpha), which in turn was higher than that of the SS (alpha alpha/alpha alpha). The emergence of this difference coincided with a developmental increase of the mean corpuscular hemoglobin concentration (MCHC) in patients with SS (alpha alpha/alpha alpha) and the decline of Hb F % under 15%. This newly observed developmental change of the MCHC could lead to increased hemolysis and anemia after the age of 5-10 years. It occurs to a smaller extent among SS (-alpha/alpha alpha) or not at all among SS (-alpha/-alpha) such that these two categories of patients have less severe hemolysis and higher hemoglobin levels at older ages. Although the proportion of Hb F was independent of alpha globin gene numbers, the absence of Hb Bart's suggested that alpha-thalassemia promotes the intracellular assembly of Hb F over Hb S tetramers. Thus, the interaction of alpha-thalassemia and Hb F in young SS patients may be more complex than revealed by Hb F levels in cell lysates. Among older SS children (greater than 7 years) alpha-thalassemia and Hb F levels exceeding 15% appear to have additive effects in diminishing the rate of hemolysis.