e16011 Background: Epidemiologic and molecular evidence have established the strong link between high-risk types of human papilloma virus and a subgroup of head and neck squamous cell carcinoma. We evaluated the frequency of HPV positivity in HNSCC and its relationship to demographic and some risk factors variables in an open case-control study. Methods: Fourteen newly diagnosed patients of squamous cell cancer of oral cavity, oropharynx, hypopharynx and larynx aged between 18-50 year were examined from 2008-2010 in hematology and Oncology Research Center of Tabriz University of Medical Sciences. HPV DNA was extracted from paraffin-embedded block of each patient for evaluating by PCR. Saliva samples of 94 control cancer free subjects were collected for DNA analysis also. Multivariable logistic regression was used to calculate odds ratio for case-control comparisons. Results: High-risk HPV was detected in 6 (42.8%) of patients and 6 (5.3%) of control subjects, which statistically was significant (P<0.0001). HPV-18 was the most frequent type both in the case and control groups. HPV-16 DNA was detected in two patients and none of control subjects. The relation between demographc and risk factor variables was not statistically significant. Conclusions: HPV infection has significant impact on HNSCC, although has been shown, HPV-16 has the greatest role, however HPV-18 could be the cause of malignant degeneration in such cancers in some communities that needs greatest caution for health care systems of such communities in making immunization program.