Head and neck squamous cell carcinoma (HNSCC) affects 30,000 in the US with oropharyngeal carcinoma (OSCC) incidence increasing 3% annually (1973-2001). OSCC's are attributed to tobacco and alcohol, but patients without risk factors develop cancer. High-risk Human Papillomavirus (HPV) DNA has been consistently detected in 20% of HNSCC's and 50% of the OSCC's revealing OSCC's infectious nature. To date case-control studies of nonsmoker/nondrinkers (NS/ND) have not been performed. The purpose of this study was to determine whether high-risk HPV infection was significantly associated with NS/ND OSCC. This case control study consistently detected HPV 14/18 in OSCC (78% cases) of NS/ND with oropharynx preponderance (86%). A sub-study analyzing tumors from intimate partners detected identical strains of integrated HPV 16 within each couple. We have identified close links between HPV and OSCC in NS/ND, this justifies early identification of this virus as it may act as a crucial marker of malignancy susceptibility.