In a family of Swiss-French descent several members in three generations had, on hemoglobin analysis, typical findings of heterozygous β-thalassemia. However, hemoglobin concentrations, red-cell morphology, iron kinetics, splenic size and clinical histories indicated that the disorder was more severe than in the usual β-thalassemia trait. The ratios of β-chain to α-chain synthesis in blood and bone marrow differed from those in β-thalassemia trait, and, most importantly, up to 70 per cent of the late normoblasts contained inclusions shown to consist of precipitated α chains. The data suggest existence of a form of thalassemia that produces a definite excess of α chains in the immature erythroid cells of simple heterozygotes. The abnormality is designated "inclusion-body β-thalassemia trait." The findings provide an apparent pathophysiologic and genetic explanation for the more severe anemia and red-cell abnormalities present in a small proportion of families with β-thalassemia trait. (N Engl J Med 290:939–943, 1974)