We have studied a four-generation (23 subjects) African-American family with β thalassemia and high fetal hemoglobin (HbF) levels. The β thalassemia in this family is due to the splicing site mutation, β IVS2+1G→A, that leads to aberrant mRNA processing and the absence of β globin. Two members of this family are homozygous for β thalassemia and are non-anemic. All family members who are heterozygous for the β IVS2+IG→A mutation have elevated HbF, with the exception of two individuals who also have severe α-globin chain deficiency. We excluded linkage with the hereditary persistence of fetal hemoglobin loci on chromosomes 6 and X. We also excluded the presence of all previously described determinants in the β globin gene cluster associated with elevated HbF production. One thalassemia allele is in the Cameroon-like (HS2)/Benin-like β globin gene cluster haplotype, and the other is in the Senegal-like (HS2)/Benin-like β globin gene cluster haplotype. We speculate that in the homozygotes, those erythroid cells that express low to absent levels of γ globin are selectively destroyed. In contrast, in the heterozygotes, the presence of the normal β globin allele would ameliorate the globin chain imbalance and thus allow survival of erythroid cells that express the abnormal transcript, leading to a typical β thalassemia phenotype. Thus, the heterocellular γ globin expression together with in vivo preferential survival of HbF-containing erythroid cells ameliorates Cooley's anemia in the β thalassemia homozygotes. It remains to be determined what sequences linked to each thalassemia allele and what trans-acting factors contribute to high HbF levels. © 2001 Wiley-Liss, Inc.