Background: Due to their chronic hypercoagulable status, thalassemic individuals are at an elevated risk of developing thromboembolic sequence consequences. The goal of the current study is to assesses the EPCR gene polymorphism and soluble EPCR in Egyptian thalassemic children and its role in hypercoagulable state. Research design and methods: Eighty children diagnosed as thalassemia major and 80 healthy youngsters as a control group. The EPCR gene was identified using a restriction fragment length polymerase chain reaction (RFLP PCR). Additionally, we assessed the soluble EPCR levels using an enzyme-linked immunosorbent assay (ELISA). Results: Frequency of 1651C-G EPCR, the GC genotype was strongly related with an increased risk of coagulation (OR = 1.83 (0.64–5.26), P = 0.0.016). In addition, soluble EPCR was considerably higher in patients with thalassemia than in controls, P value <0.001. Our study revealed significance difference between soluble EPCR and different genotypes. Conclusion: Polymorphisms in the EPCR gene and an elevated soluble EPCR level in patients with β- thalassemia major may contribute to these patients’ hemostatic derangement in thalassemic Egyptian children.