The pathophysiology and clinical severity of β‐thalassemia are related to the degree of α/non‐α‐chain imbalance. A triplicated α‐globin gene locus can exacerbate effects of excess α‐chains caused by a defective β‐globin gene, although this is not observed in all cases. Extensive studies on this condition are lacking. We report a group of 17 patients who are heterozygous for both the ααα^anti‐3.7 allele and a mutation in the β‐globin gene cluster. Their clinical phenotypes varied: six had mild anemia with microcytosis and hypochromia, while 11 had more severe anemia with splenomegaly requiring splenectomy (three cases) and blood transfusions (four cases). Different phenotypes were also evident in the presence of the same β‐thalassemia mutation: in one family, two individuals had the same α‐ and β‐globin genotypes but presented with different hematologic phenotypes. In addition, the complex interaction involving a triplicated α‐globin gene, β³⁹‐ and δ⁺²⁷‐thalassemia mutations is studied in a family with two siblings presenting with hemolytic anemia, normal Hb A₂ and increased Hb F. Analysis of this series of patients suggests that additional genetic determinants play a role in modulating phenotypic expression in individuals with identical α‐ and β‐globin genotypes. Interaction with a triplicated α‐gene can play a role in the clinical presentation of patients with defective β‐globin gene expression and should be considered in the diagnosis of atypical cases. Am. J. Hematol. 55:83‐88, 1997. © 1997 Wiley‐Liss, Inc.