The -thalassemia syndromes are a heterogeneous group of genetic disorders characterized by reduced or absent expression of the -globin gene. To date, over 300 -thalassemia alleles have been characterized in or around the -globin region. Thalassemia major is severe anemia necessitating chronic blood transfusions, splenectomy, iron chelation therapy, and bone marrow transplantation. Usually thalassemia major results from homozygosity or compound heterozygosity for severe  O -and/or  +thalassemia mutations. Thalassemia intermedia is a clinical diagnosis that describes a symptomatic but less severe condition than -thalassemia major. -thalassemia intermedia may arise from several different combinations of ␣and/or -thalassemia mutations. Heterozygous -thalassemia is typically characterized by a mild microcytic hypochromic anemia without any significant clinical implications. In this report, we describe a 63-year-old Africian American woman with asymptomatic homozygous -thalassemia, who seems to carry 2 copies of the -29 mutation in the promoter region of the -globin gene. Her elevated hemoglobin F level of 83% was associated with heterozygosity for the Xmn I polymorphism upstream of the G ␥-globin gene. Southern blot analysis at the ␣-globin locus did not show any deletion that would account for the mildness of her phenotype. Therefore, homozygosity for the -29 mutation along with the Xmn I polymorphism appears to confer an extremely mild -thalassemia phenotype. This observation has important implica-tions in the prenatal diagnosis and genetic counseling of families segregating this type of genetic defect. Am.