von Willebrand disease (VWD) is a most common inherited bleeding disorder. von Willebrand factor (VWF) exists as an extracellular adaptor molecule and generally involves in the hemostasis mechanism through binding with GP (Glycoprotein) Ib-IX-V platelet receptor. Clinical phenotype of bleeding disorders modulated to a decrease in bleeding symptoms by thrombogenic mutations. We made an attempt to investigate the impact of thrombogenic mutations/polymorphisms on the clinical phenotype of 114 different types of patients with VWD, and 120 healthy controls were screened for methylenetetrahydrofolate reductase (MTHFR) 677C/T, factor V (FV) Leiden (1691G/A), beta(3) integrin (HPA-I) (Human platelets antigen-I) gene (1565T/C), and prothrombin 20210G/A mutations. Genotypic analysis was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism. Forty-five patients (39.5%) were found to be positive for at least one of the prothrombotic risk factors screened. Prothrombin 20210G/A was not found in any patient with VWD as well as healthy control. Eight patients with VWD were carrying the defective alleles of different thrombogenic markers, showing milder phenotypes than expected. A high prevalence was observed for MTHFR 677C/T (677C/C 73.6%, 677C/T 24.6%, 677T/T 1.8%) and PLA1/A2 (1565T/T 88.6%, 1565T/C 10.5%, 1565C/C 0.87%) polymorphism followed by FV Leiden (1691G/G 97.4%, 1691G/ A 2.6%, 1691A/A 0.00%) in patients with VWD with allelic frequencies 11.4% (677T), 5% (1565C), and 1.3% (1691A). Hence, we concluded that thrombophilic markers were seen to be influencing the clinical phenotypes of patients with VWD.