This study utilized comprehensive salivary analysis to evaluate biochemical and immunological parameters in the saliva of oral squamous cell carcinoma (OSCC) patients. Whole saliva was collected from 25 otherwise healthy OSCC patients and compared to 25 healthy, age- and gender-matched individuals. All OSCC lesions were located at the lateral aspect of the mobile tongue. The salivary parameters analyzed included: sodium (Na), potassium (K), calcium (Ca), inorganic phosphate (P), magnesium (Mg), total protein (TP), albumin (Alb), lactate dehydrogenase (LDH), amylase (Amy), total immunoglobulin G (IgG), secretory immunoglobulin A (Sec. IgA), epidermal growth factor, insulin growth factor I (IGF-I) and metalloproteinases MMP-2 and MMP-9. In cancer patients, salivary median total protein concentration was significantly higher by 26% (P = 0.01), as were concentrations of Na, Ca, P and Mg by 14% (P = 0.05), 59% (P = 0.05), 39% (P = 0.08) and 28% (P = 0.12), respectively. Amy and K concentrations were lower by 25% (P = 0.12) and 15% (P = 0.03), respectively. Alb was 108% higher (P = 0.0007), as were salivary LDH (88%, P = 0.002) and total IgG (125%, P = 0.01), while Sec. IgA was lower by 45% (P = 0.001). Concentrations of IGF, MMP-2 and MMP-9 were significantly higher by 117% (P = 0.03), 75% (P = 0.0003) and 35% (P = 0.05), respectively. Comprehensive salivary analysis revealed an overall altered salivary composition in OSCC, indicating a compromised oral environment in these patients and suggesting salivary analysis as a new diagnostic tool for oral cancer. Local therapeutic agents can be easily applied to the oral mucosa, altering its “bathing medium”–the saliva.