Sickle cell disease (SCD) is a group of genetic disorders of hemoglobin that causes multisystem morbidity and an increased risk of early death. Vascular complications are an important aspect of sickle cell anemia, although there is controversial evidence surrounding the role of thrombosis in the complication. Among the crucial inherited risk factors are factor V Leiden (G1619A) and prothrombin gene G20210A mutations. The purpose of the current study was to detect the presence of factor V gene G1691A mutation and prothrombin G20210A mutation as well known risk factors for thrombophilia in sickle cell patients and to evaluate the significance of their association with vasoocclusion complications in those patients. The study was conducted on fifty SCD patients and fifty age and sex matched healthy individuals as a control group. Polymerase chain reaction Restriction Fragment Length Polymorphism (PCR-RFLP) technique was performed for the detection of factor V Leiden and prothrombin gene mutations. Factor V Leiden mutation was detected in 1/50 (2%) of the patients, similarly it was detected in 1/50 (2%) of the control group. Prothrombin G20210A mutation was significantly higher in SCD patients 31/50 (62%) than in control group 1/50 (2%) (p<0.001). In the present work, patients with sickle cell disease did not show increased frequency of factor V Leiden mutation in comparison to normal controls. They showed significantly increased frequency of prothrombin gene mutation. Both factor V Leiden and prothrombin gene mutations were not associated with the risk of developing thrombosis in SCD patients. Many risk factors are involved in the development of sickle cell vasoocclusion including HbS polymerization, sickle cell deformability, sickle blood viscosity, sickle-endothelial cell adherence, endothelial cell activation, hemostatic activation and low circulating levels of protein C and protein S. Among these interrelated risk factors it may be difficult to show significance of prothrombin gene mutation on frequency of thrombotic attacks but indeed it is possible that this mutation may increase the severity of the attacks and this should be further studied. The high frequency of prothrombin gene mutation in patients with sickle cell disease suggests the potential importance of the screening of thrombophilic mutations to attempt prevention of occlusive disorders by antithrombotic therapy and to study their correlation with the severity of venoocclusive crises and not only their frequency.