BACKGROUND: OPMDs carry an increased risk of progression to oral squamous cell carcinoma (OSCC), and microbial dysbiosis has been linked to this progression, though prior work is largely limited to species level resolution. Whole genome shotgun metagenomics enables species, functional and strain level characterization providing greater insight into microbial factors driving malignant transformation. METHODS: Oral rinse samples from OPMD patients (n=85) and non-OPMD participants (n=26) were collected and DNA extracted. The raw sequencing reads were quality filtered and host decontaminated using Kneaddata. The trimmed reads were further assessed for taxonomic and functional profiling using Meteor providing basis for ongoing strain level characterization. Differential abundance analyses were performed using MaAsLin3 while adjusting for age, sex, smoking status, alcohol consumption, oral hygiene and dysplasia. RESULTS: OPMD samples exhibited greater microbial alpha diversity than non-OPMD participants (Shannon index, P = 0.01) and distinct microbial community composition (Bray–Curtis PERMANOVA, P = 0.003). While Differential Abundant Analysis at species level revealed smoking as one of the strongest clinical factors influencing both taxonomic and functional landscape. Taxonomic Analysis shows enrichment of key species in OPMD such as Porphyromonas pasteri, Neisseria species. While functional analysis showed enrichment of antimicrobial resistance determinants (β-lactam, tetracycline, aminoglycoside) and metabolic pathways such as lactate consumption. CONCLUSION: Altogether, these findings demonstrate significant altered oral microbiome at different levels in OPMD patients relative to non-OPMD participants, supporting a potential role in disease progression. Ongoing strain level reconstruction and metabolite profiling aims to identify strain specific contributors and novel microbial biomarkers for OPMD.