This study provides further insights into the multiple roles of KLF1 in erythropoiesis and highlights the idea that a subset of KLF1 mutations may contribute to the severity of the thalassemia phenotype, thus reinforcing the relevant implications of KLF1 screening for genetic counseling and for the effectiveness of prevention screening programs for hemoglobinopathies. This evidence concerns the gene KLF1 and thalassemia.