Objectives To determine the levels of carbohydrate antigen 125 (CA125) and tissue polypeptide-specific antigen (TPS) in saliva of patients with oral squamous cell carcinoma (OSCC) and patients with nonneoplastic disease of the oral cavity, and to investigate their diagnostic value and their relationship with pathological grade and clinical stage. Methods A total of 97 hospitalized patients with OSCC, 36 patients with nonneoplastic disease of the oral cavity and 50 healthy individuals were included in this investigation. Mixed saliva was collected from these patients and the healthy controls before treatment. Saliva samples were analyzed by enzyme-linked immunosorbent assay (ELISA). Results The saliva CA125 and TPS concentrations were significantly higher in patients with OSCC than in patients with nonneoplastic disease and healthy controls, but not significantly different between patients with nonneoplastic disease and controls. Neither the saliva CA125 nor the TPS level was correlated with pathological grade and clinical stage. The sensitivity, specificity and accuracy of saliva CA125 and TPS for the diagnosis of OSCC were 80.0%, 66.0%, 75.7%, and 82.1%, 74.0%, 79.3%, respectively. When CA125 and TPS were analyzed independently, there was no significant difference in sensitivity, specificity and accuracy between the two markers. When CA125 and TPS were analyzed in combination, there was no significant difference in sensitivity, specificity and accuracy between independent detection and combined detection. Conclusions The saliva CA125 and TPS concentrations were elevated in patients with OSCC. CA125 and TPS may prove to be useful tumor markers in OSCC.