β-Type hemoglobinopathies are characterized by vast phenotypic diversity as far as disease severity is concerned, while differences have also been observed in hydroxyurea (HU) treatment efficacy. These differences are partly attributed to the residual expression of fetal hemoglobin (HbF) in adulthood. The Krüppel-like family of transcription factors (KLFs) are a set of zinc finger DNA-binding proteins which play a major role in HbF regulation. Here, we explored the possible association of variants in gene family members with response to HU treatment efficacy and disease severity in β-hemoglobinopathies patients. Six tag single nucleotide polymorphisms, located in four  genes, namely and , were analyzed in 110 β-thalassemia major patients (TDT), 18 nontransfusion dependent β-thalassemia patients (NTDT), 82 sickle cell disease/β-thalassemia compound heterozygous patients and 85 healthy individuals as controls. Our findings show that a genomic variant (rs2236599) is associated with HU treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients and two genomic variants (rs980112, rs3191333) are associated with persistent HbF levels in NTDT patients. Our findings provide evidence that genomic variants located in gene may be considered as potential prognostic biomarkers of β-thalassemia clinical severity and an additional variant in gene as a pharmacogenomic biomarker, predicting response to HU treatment.