Routine hematology, DEAE-cellulose chromatography, and the technique ofin vitrosynthesis of hemoglobin chains were used to evaluate possible relationships between the quantities of theβchain variants Leslie, S, C, and N-Baltimore in heterozygotes, the hematological parameters, and the ratios of the synthesis ofαandβchains. Decreased quantities of all variants (except IIb. N-Baltimore) are associated with lowered MCV and MCH values and with nonα/αchain ratios between 1.2 and 2.4. Data from similar studies in 2–3 year old Hb S or Hb C heterozygotes who had about 5% Hb Bart's (γ4) at birth showed low percentages ofβchain variant (30% or less), decreased MCV and MCH values and an average nonα/αchain ratio of 1.79 for the AS children and of 1.73 for the AC children. Their mothers showed either similar deficiencies (2 of 8 cases) or were only mildly affected. These data are explained by assuming the presence of only one active a chain locus on each chromosoae (the -α/-αarrangement). This leads to a deficient a chain production resulting, among others, in microcytosis, decreased levels of (some)βchain variants, chain imbalance, but not in an overt anemia. Persons with the -α/ααarrangement (found in 6 of the 8 mothers) showed intermediate values.Studies of a large number of families showed a trimodality for the hemoglobins Leslie, S, and C which is readily explained by seeming the presence of a different number of active Hbαgene loci (average values for IIb S in heterozygotes with theαα/ααarrangement: 41.2%; with the -α/ααarrangement: 35.4%; with the -α/-αarrangement: 28.1%).The proposed genetic model is based on variation in a gene dosage and is different from that explaining the a thalassemia condition of the East Asian populations; mechanism responsible for the decreased percentages ofβchain variants in heterozygotes are discussed; some are presently under active investigation.