Squamous cell carcinoma of the oropharynx (SCCOP) is characterized by local tumor aggressiveness requiring morbid local-regional therapies with poor survival and high recurrence rates. Despite declining smoking prevalence, the incidence of SCCOP is stagnant and incidence is increasing in young adults. These trends may be due to the rising prevalence of oncogenic human papillomavirus (HPV) in the population. HPV+ SCCOP is a distinct epidemiologic, clinical, and molecular disease with potentially unique clinical behavior and treatment responses. Identification of those needing treatment intensification and those able to benefit from reduction of treatment intensity is critical to more effective and less morbid treatment. Oncogenic subtypes of HPV, principally type 16, are critical etiologic factors in a distinct subset of head and neck cancers, chiefly SCCOP. Inflammation/immune responses which control the HPV clearance and escape of immune surveillance may contribute to the risk and possibly the outcomes of HPV-associated SCCOP. In addition, the unique pattern of genetic profiles in HPV+ SCCOP might confound correlations with clinical outcome. Therefore, we speculate that genetic polymorphisms in the likely functional regions of these genes may pose individual difference in susceptibility to HPV infection and constitute the confounding effect on HPV-related clinical outcomes. In this case-case comparison study, the study subjects will be 300 patients with incident SCCOP retrospectively identified from an existing molecular epidemiologic study of squamous cell carcinoma of the head and neck. The specific aims for this R03 project are: 1) to establish a database with demographic, clinical and follow-up information, genotypes of the polymorphisms, and HPV16 DNA tumor status on 300 of these SCCOP patients, 2) to assess genotypes of Inflammation/immune response related genes involved in both pro- and anti-inflammation pathways as markers of susceptibility for HPV16 association among patients with SCCOP, and 3) To determine if variants of these genes in both pro- and anti-inflammation pathways modify HPV-related clinical outcomes (recurrence and survival) of SCCOP patients. The long-term goal of this project is to use these genetic polymorphisms as surrogate markers to help identify individuals at high risk of HPV16 infection and/or at risk for poor outcomes in order to better individualize SCCOP prevention and treatment as well as improve of both survival and quality of life.