Hemoglobin E beta-thalassemia is an important cause of childhood chronic disease in Southeast Asia. It is characterized by the presence of hemoglobin E and F, and the amount of hemoglobin E ranges from 35% to 75%. The patients are generally classified as having thalassemia intermedia because they have inherited a beta-thalassemia allele and hemoglobin E, which acts as a mild beta+-thalassemia. However, a remarkable variability in the clinical expression, ranging from a mild form of thalassemia intermedia to transfusion-dependent conditions, is observed. Severe hemoglobin E beta-thalassemia may have clinical features of thalassemia major. Phenotypes of thalassemia major can be predicted from the early onset of clinical symptoms and the requirement of regular blood transfusion from infancy for survival. Coinheritance of alpha-thalassemia alleviated the severity of beta-thalassemia disease in patients with at least one allele of mild beta-thalassemia genotype.