BackgroundThe oral microbiome, particularly Fusobacterium nucleatum (Fn), has been implicated in head and neck cancers (HNC), influencing local immunity and Human Papillomavirus (HPV) status. Here, we evaluated the presence of Fn and its association with HPV infection, TERT promoter (TERTp) mutations, and patient outcomes.Materials and MethodsWe analyzed 94 formalin-fixed paraffin-embedded (FFPE) tumor tissues from HNC patients previously evaluated for TERTp mutations. Fn DNA was detected using droplet digital PCR (ddPCR), and HPV status was determined via p16 immunohistochemistry in pre-treatment samples. Associations between Fn presence, clinicopathological features, HPV, and TERTp mutation status were assessed.ResultsTumors primarily originated from the oropharynx (70.2%) and oral cavity (29.8%). Tobacco and alcohol use were reported in 87.2% and 79.8% of cases, respectively. Fn was present in 59.6% of cases, with higher prevalence in oropharyngeal (62.1%) than oral cavity (53.6%) tumors. No significant associations were found between Fn and clinicopathological features, TERTp, or HPV status. However, patients with Fn positivity showed significantly improved cancer-specific survival (61.5% vs. 39.1%, p = 0.013), similar to HPV-positive patients (72.7% vs. 42.7%, p = 0.014).ConclusionThe presence of Fusobacterium nucleatum in HNC correlates with longer survival, highlighting its potential as a prognostic marker.