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Objectives: The pathogenesis of oral cavity cancers is complex. We tested the hypothesis that oral microbiota dysbiosis is associated with oral cavity cancer., Materials and Methods: Patients with primary oral cavity cancer who met the inclusion and exclusion criteria were included in the study. Matching healthy individuals were recruited as controls. Data on socio-demographic and behavioral factors, self-reported periodontal measures and habits, and current dental status were collected using a structured questionnaire and periodontal chartings. In addition to self-reported oral health measures, each participant received a standard and detailed clinical examination. DNA was extracted from saliva samples from patients and healthy controls. Next-generation sequencing was performed by targeting V3-V4 gene regions of the 16 S rRNA with subsequent bioinformatic analyses., Results: Patients with oral cavity cancers had a lower quality of oral health than healthy controls. Proteobacteria, Aggregatibacter, Haemophilus, and Neisseria decreased, while Firmicutes, Bacteroidetes, Actinobacteria, Lactobacillus, Gemella, and Fusobacteria increased in oral cancer patients. At the species level, C. durum, L. umeaens, N. subflava, A. massiliensis, and V. dispar were significantly lower, while G. haemolysans was significantly increased (p < 0.05). Major periodontopathogens associated with periodontal disease (P. gingivalis and F.nucleatum) increased 6.5- and 2.8-fold, respectively., Conclusion: These data suggested that patients with oral cancer had worse oral health conditions and a distinct oral microbiome composition that is affected by personal daily habits and may be associated with the pathogenicity of the disease and interspecies interactions., Clinical Relevance: This paper demonstrates the link between oral bacteria and oral cancers, identifying mechanistic interactions between species of oral microbiome., (© 2024. The Author(s).)