Background: Sickle cell disease (SCD) is a common form of hereditary disease of an autosomal recessive inheritance with a highly variable phenotype. Interindividual variation in Fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. One of the genetic determinants that is thought to cause a modest increase in HbF level is the Xmn1 γG-158 C/T gene polymorphism. Objectives: This study aimed to investigate the prevalence of the Xmn1 γG-158 (C/T) gene polymorphism in Egyptian SCD patients and the association between this polymorphism and HbF level .Design and setting: A cross-sectional case control study which was conducted on 111 SCD patients. Each patient was subjected to full medical history taking, through medical examination, routine laboratory investigation and genotyping of Xmn1 γG-158 (C/T) genetic polymorphism by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Results: Xmn1 positive site was found in nine 9 (8.1%) of SCD patients. The wild genotype Xmn1(-/-) was the predominant state; found in 102 (91.9%) of SCD patients. The heteromutant genotype Xmn1(+/-) was detected in 8 (7.2%) while the homomutant genotype Xmn1(+/+) was found in 1(0.9%) of the SCD patients. Fetal Hb level, total hemoglobin and mean corpuscular volume were significant higher in the mutant genotypes harboring patients with p value <0.05. No statistical significant different was encountred as regards clinical history (p>0.05). Conclusions: The study demonstrated that Egyptian SCD patients have low frequency of mutant genotypes for Xmn1 γG-158 (C/T) gene polymorphism whether in heterozygous (+/-) or homozygous (+/+) state .The presence of Xmn1 γG-158 (C/T) gene polymorphism has positive influence on Hb F level.