Abstract Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide, and new protocols for routine and early detection are required. Raman spectroscopy is an optical based method that can provide sensitive and non-invasive real time detailed information on the biochemical content of a sample like saliva, through the unique vibrations of its constituent molecules and this is sensitive to changes associated with disease. A comprehensive systematic review of the available scientific literature related to Raman spectroscopy of human saliva for diagnosis of OSCC was performed. The 785 nm laser line was most applied wavelength along with principal components analysis associated with linear discriminant analysis. The main salivary components possibly associated with the presence of OSCC were proteins and lipids. Measurement in the liquid physical state, and with no addition of nanoparticles for signal enhancement, seemed to best conserve the salivary integrity. However, in terms of sampling protocols, no differentiation was generally made between stimulated and non-stimulated saliva. Raman spectroscopy of saliva holds a promising future for clinical applications such as early detection of OSCC. However, more systematic analyses are still required for a better elucidation regarding sampling procedure, storage and degradation
