Background: Oral Potentially Malignant Disorders (OPMDs) are lesions that have the potential to transform into oral cancer. Various genetic, environmental, and lifestyle factors have been implicated in the development of these lesions. Recent studies have suggested a possible association between ABO blood groups, Rh factor, and the susceptibility to OPMDs. This study aims to investigate the relationship between ABO blood group and Rh factor with the prevalence of OPMDs in a selected population.Materials and Methods: A cross-sectional study was conducted on 500 patients were categorized based on their ABO blood group and Rh factor. The presence of OPMDs was diagnosed based on clinical examination and histopathological confirmation. Statistical analysis was performed to assess the association between blood groups, Rh factor, and the occurrence of OPMDs. Arbitrary values were assigned to represent the prevalence of OPMDs in different blood groups and Rh factor categories.Results: The study revealed a significant association between the ABO blood group and the prevalence of OPMDs (p < 0.05). Patients with blood group A showed the highest prevalence (30%) of OPMDs, followed by blood group B (25%), AB (20%), and O (15%). The Rh-positive group exhibited a higher prevalence (65%) of OPMDs compared to the Rh-negative group (35%). The most common OPMD observed was leukoplakia, followed by erythroplakia and oral submucous fibrosis.Conclusion: The findings of this study suggest a significant association between ABO blood group, Rh factor, and the risk of developing OPMDs. Individuals with blood group A and Rh-positive status may be at a higher risk of developing these lesions. Further large-scale studies are warranted to confirm these findings and to understand the underlying mechanisms.