Whereas hemoglobin (Hb) E-β thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and β-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-β thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with β-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-β thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-β thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-β thalassemia is similar to that observed in patients with β-thalassemia. These data, in the only cohort of patients with Hb E-β thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with β-thalassemia may be generally applicable to those with Hb E-β thalassemia. Further quantitative studies in both nontransfused and transfused patients will be necessary to permit firm conclusions.