Population surveys and family studies among 568 members of nine ethnic groups in southern India identified 15 homozygotes for sickle hemoglobin (HbS)who had mild clinical and hematological manifestations with high levels of fetal hemoglobin (mean=20%, range 8-36%) in a heterogeneous red cell distribution. In one family, the heterozygous mother had a hemoglobin pattern consistent with a form of the heterocellular hereditary persistence of fetal hemoglobin. Sickle cell trait was found in 153(27%) of those studied. Chromatographic quantitation of the hemoglobin fractions in these heterozygotes showed a trimodal distribution of the proportion of HB Sexplicable by a genetic model postulating the presence of genotypes with two (-alpha/-alpha), three (-alpha/alpha alpha) and four (alpha alpha/alpha alpha) active alpha-globin genes. Globin synthesis studies in four heterozygotes believed to have two active alpha-globin genes demonstrated an alpha/non-alpha total activity ratio (0.57) consistent with this model.