ABSTRACT We hypothesize that oral microbiota influence squamous cell head and neck cancer (SCHNC) development, potentially related to carcinogen metabolism. The human oral cavity hosts a diverse microbiota, including bacteria and fungi. In the previous R01 cycle, we made the novel discovery that oral bacteria are associated with SCHNC. In this competitive R01 renewal application, we focus on oral fungi (the mycobiome). Oral fungi activate carcinogens and promote inflammation and oral carcinogenesis. Fungi are commonly isolated from oral cancers and pre-cancers. Furthermore, patients with fungal Candida clinical infection have increased risk for SCHNC. Despite this evidence, there is limited knowledge about the direct relationship of oral fungi with development of SCHNC in the general population. Our ultimate goal is to identify microbial determinants of SCHNC which may lead to novel microbially-based approaches for SCHNC prevention. Our specific aims are 1) to test if oral fungi influence the development of SCHNC, 2) to test if oral fungi and bacteria jointly influence the development of this disease and 3) to determine whether oral fungi and bacteria contribute to oral microbial functional pathways for carcinogen metabolism. The study includes 339 incident SCHNC cases and 339 nested controls in the NCI-PLCO, ACS-Cancer Prevention Study-II and the Southern Community Cohort Study. More than 468,000 SCHNC cases and 323,000 related deaths occur annually worldwide. Knowledge gained from this study will increase our understanding of the etiology of SCHNC. The study will serve to identify high- risk subjects, based on oral microbial status. Pre-diagnostic microbiota found in this prospective study may lead to new microbial approaches for personalized prevention of this disease.