Simple SummaryThe impact of the oral microbiome on head and neck cancer is poorly understood. Better characterization of its impact may improve our understanding of the development of the disease and management of disease outcomes. This case–control study seeks to identify differences in the oral microbiome between patients who have head and neck cancer and controls who do not. Furthermore, we seek to identify types of microbial communities based upon abundance and compare those types with survival outcomes. We found that two commensal microbes that are associated with pathologic states when overgrown were more common in head and neck cancer cases than the controls. Furthermore, we identified two community types within our population. The community type with previously established pathogenic microbes had a lower yet non-significant hazard of death compared to the community with a higher abundance of commensal organisms.AbstractThe impact of the oral microbiome on head and neck cancer pathogenesis and outcomes requires further study. 16s rRNA was isolated and amplified from pre-treatment oral wash samples for 52 cases and 102 controls. The sequences were binned into operational taxonomic units (OTUs) at the genus level. Diversity metrics and significant associations between OTUs and case status were assessed. The samples were binned into community types using Dirichlet multinomial models, and survival outcomes were assessed by community type. Twelve OTUs from the phyla Firmicutes, Proteobacteria, and Acinetobacter were found to differ significantly between the cases and the controls. Beta-diversity was significantly higher between the cases than between the controls (p< 0.01). Two community types were identified based on the predominant sets of OTUs within our study population. The community type with a higher abundance of periodontitis-associated bacteria was more likely to be present in the cases (p< 0.01), in older patients (p< 0.01), and in smokers (p< 0.01). Significant differences between the cases and the controls in community type, beta-diversity, and OTUs indicate that the oral microbiome may play a role in HNSCC.