The role of genetic prothrombotic risk factors on the clinical phenotype of haemphilia ; namely, Factor V Leiden (G1691A), prothrombin G20210A, Methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C) gene polymorphisms was studied in 101 Egyptian haemphilia patients (of which 25 patients showed mild clinical phenotype inspite of having moderate or severe laboratory factor VIII level). Our aim was to study the incidence of the most common prothrombotic risk factors among patients with hemophilia and their impact on the clinical phenotype; annual bleeding frequency and severity of hemophilic arthropathy. Patients were diagnosed by FVIII and FIX activity assays. Genotyping was carried out using real-time PCR assay based on allele-specific fluorescent oligonucleotides that contain a 3’ minor groove binding (MGB) group. Our study revealed 3%, 14%, 41.5% and 58.4% patients showing Prothrombin G20210A, factor V leiden, MTHFR (C677T) and MTHFR (A1298C) mutations respectively in the studied Egyptian haemophilia patients. Inspite of non significant statistical analysis, the presence of heterozygous cases of prothrombin G20210A or Factor V leiden was always associated with mild or moderate clinical presentation of haemphilia and never with severe presentation. This finding supports the hypothesis of the protective effect of the prothrombotic genes (P G20210A and factor V Leiden) on the clinical presentation of haemophilia patients. Statistical analysis revealed that the lowest bleeding frequency among the studied patients (< once/ month) was encountered among the patients with two heterozygous variants irrespective to the involved genes. In addition, our finding that the incidence of haemarthrosis was significantly higher among patients with wild genotype of prothrombin gene and factor V Leiden and that the average number of affected joints was significantly higher among patients with wild prothrombin gene than heterozygous patients, all these data collectively strongly points to the cumulative effect of these prothrombotic polymorphisms in amelioration of the severity of bleeding in hemophilic. The most prominent effect is that of prothrombin G20210A and factor V leiden. . Findings of MTHFR C677A & A1298C gene polymorphisms are less conclusive and large scale multicenter or meta-analysis studies are needed to have accurate final conclusions.