alpha-Thalassemia is a common genetic disorder in Iran. However, no comprehensive data on epidemiology of severe forms of alpha-thalassemia, including hemoglobin H (HbH) or hydrops fetalis, is available in this population. This is a first case report of an Iranian family with large number of HbH individuals. The proband is a 48-year-old woman, referred to our center with anemia and no history of previous blood transfusions. Similar clinical phenotype has been observed in all of her 5 siblings, 2 of her 4 children, and her granddaughter, whose parents are first cousins. A reverse hybridization assay covering 21 alpha globin mutations was performed to determine the genotype in 11 members of this family and a fetus. HbH genotype was identified in 9 individuals, representing 3 generations, including a fetus. The high prevalence of alpha-thalassemia carriers together with the high rate of consanguineous marriages could lead to a large number of individuals with HbH or even hydrops fetalis in Iranian families. Therefore, to avoid the risk of having affected offspring, carrier detection, genetic counseling, and prenatal diagnosis would be of vital importance for individuals with low red blood cell (RBC) indices, normal iron status, and normal HbA(2) level, who are suspected to be alpha-thalassemia carriers.