Statements of Problems: Head and neck squamous cell carcinoma is the sixth most common cancer worldwide. Inactivation of one or more components of the P53 network is a common event in human neoplasia. In head and neck carcinoma, disability of P53, occurs in a high proportion of cases by mutation in the P53 gene. Cause of inactivation, such as the presence of human papilloma virus (HPV) has also been recognized.Purpose: The aim of this study was to examine co-incidence of human papilloma viruses type 16.18 and P53 alteration in oral squamous cell carcinoma.Materials and Methods: Of 42 oral tissue specimen (36 oral squmous cell carcinoma and 6 oral verrucous carcinoma) including 25 men and 17 women which were visited in Isfahan University, School of Dentistry in 1369-1383, multiple serial sections from formalin fixed, paraffin embedded tissues were prepared. Immunohistochemical detection of P53 protein was carried out by a standard Avidin-Biotin peroxidase procedure. Standard PCR analysis was used for detection of DNA HPV 16 and 18. The data were analyzed with Chi-Square and Fischer Exact tests.Results: General HPV sequence was detected in 21 out 42 (50%) tumor specimens. HPV 16 and 18 sequences were detected in 11 of 42 (26.2%) tumor specimens. Over expression of P53 was observed in 23 of 42 (54.8%) oral cancers. Ten of the 21 HPV Positive tumor specimens showed alterations in P53 protein expression. In spite of no significant correlation between observation of general HPV genome and P53 alteration, a significant correlation between HPV 16 and 18 and P53 alteration existed.Conclusion: In present study, we could not show any significant correlation between general HPV genome and intensity of P53 expression. A remarkable correlation between HPV 16 and 18 and over expression of P53 protein was observed. So, the results of this study remained controversial and we suggest a more precise modified procedure to be performed on this subject. So, frozen technique and more samples would be necessary for further study in future.Key words: PCR, IHC, HPV, HPV16, HPV18, P53, Correlation