The thalassemias are genetically complex and usually autosomal recessive. We describe 5 unrelated individuals with non-transfusion-dependent β-thalassemia (NTDT), some with apparently dominant transmission, because of a single β-thalassemia mutation coinherited with a triplicated α-globin locus. Each had an initial, incorrect diagnosis of β-thalassemia trait. The correct diagnosis of NTDT was made at a mean of 7 years of age. Despite reports of this compound genotype causing NTDT, it remains unfamiliar to many clinicians. To increase awareness, we highlight its varied and sometimes subtle clinical and laboratory features and the need for comprehensive genetic testing for timely and correct diagnosis.