ObjectivesOral squamous cell carcinoma (OSCC) is the most common head and neck malignancy and tobacco-related cancers account for a significant portion of all oral cancers. Cancer patients often suffer from cachexia, which contributes significantly to mortality. Leptin is a protein released by adipocytes identified to play an important role in obesity and inflammation. The present study aimed to quantify and compare salivary and serum leptin in tobacco smokers and OSCC. Materials and MethodsThe present prospective case-control study enrolled 42 subjects divided equally among OSCC and tobacco smokers without oral lesions (TS). Both saliva and blood were collected from each subject and leptin levels were determined using enzyme-linked immunosorbent assay. The data obtained were analysed using Mann Whitney U, Kruskal Wallis, Friedman, and Spearman correlation tests (p < 0.05). ResultsA significant reduction in both salivary and serum leptin levels in OSCC was observed (p < 0.001, 0.002 respectively). In addition, significant reductions in weight and body mass index were also observed during follow-ups at 3, 6, and 9 months (p < 0.001 for both). ConclusionsReduced salivary and serum leptin levels in OSCC proved that it is an important diagnostic marker, with non-invasive saliva measurement being more patient-friendly. Future multicentric studies with higher samples in OSCC subgroups are warranted. Clinical RelevanceLeptin reduction in oral squamous cell carcinoma proved to be an important diagnostic marker. Non-invasive salivary techniques could be employed in mass screening programmes. The significant correlation between leptin and BMI also shed insight into the overall well-being of the patient.