Oral squamous cell carcinoma is the most common malignant neoplasm of oral mucosa, representing more than 90%. Tobacco and alcohol has been considered as the classical risk factors. Human papilloma Virus has been proposed as an etiological risk factor since 2007. Thirty five cases diagnosed with OC their ages and gender matched with controls were enrolled in this study. Fifty-five un-stimulated whole saliva samples (35 OC and 20 apparently health subjects) were collected. DNA was purified from exfoliate cells to amplify HPV-DNA using HPV-L1 gene sequence primers by polymerase chain reaction (PCR) method, the genotyping was performed using direct sequencing method. Mean age was 52.23±13.73 years in cases (range: 17-70 years) while in controls was 50.55±12.5 years (range: 24-74 years).Forty-six percent (16/35) of OC patients was positive for detection of HPV DNA (P<0.001). The most frequent type in patient group was HPV-18 type accounting for (31%) of cases (P<0.05). The prevalence rate of HPV was significantly higher among younger ages (<50 years) with P=0.042. In addition the prevalence of HPV was higher with other variables with no significant association: male, tongue tissue, and grade I differentiation, and squamous cell carcinoma (P=0.150, P=0.678, P=0.983, ad P=0.765 respectively).