Objectives: The aim of this study was to determine the association between HR-HPV and p53 gene mutation among Sudanese oral cancer patients. Methodology: In this retrospective study 200 patients with oral lesions were screened by molecular methods (PCR) for the presence of HR-HPV subtypes and Immunohistochemistery for presence of p53 gene mutation. Of the 200 patients, 100/200 were patients with oral cancer (ascertained as case group) and 100/200 were patients with non-neoplastic oral lesions (ascertained as control group). Results: Out of the 200 patients, 12/200 (6%) were found with HR-HPV infection. Of the 12 positive patients, 10/12 (83.3%) were among cases and the remaining 2/12 (16.7%) were among control group, HPV16 was the most prevalent type. None of the sample of patients with benign tumor with positive HPV showed p53 gene mutation. From three samples obtained from patients with oral cancer who were positive HPV showed (30%) had mutations in the p53 gene. The chi- square test was shown to have significant differences between the oral cancer with HPV infection and the presence of p53 mutation Conclusion: HPV is a risk factor for oral cancer, and not always that the incidence of cancer is caused by mutations in gene.