Head and neck cancer (HNC) includes malignant tumours that most commonly arise from the oral mucosa or lining of the head and neck regions. They are characterized according to their primary site of origin as malignancies of the nasal cavity and paranasal sinuses, pharynx, larynx, salivary glands and oral cavity. The majority of these neoplasms are epithelial tumours, among them the 90% are squamous cell carcinomas (SCC). HNC including the Oral Squamous cell carcinoma (OSCC), is the sixth most common neoplasia worldwide with an incidence estimated at 650,000 cases and 330,000 deaths per year. Despite all of the diagnostic and therapeutic advances, the 5-year survival rate remains relatively poor, around 50%. The typically late diagnosis usually requires surgical intervention, often followed by adjuvant radiotherapy (RT) and/or chemotherapy (CT) treatment. Ionizing radiation is known to increase the expression of a number of cytokines involved in inflammation and wound healing. Inflammation has become an important hallmark of cancer, the chronic inflammatory microenvironment is associated with the release of various pro-inflammatory and anti-inflammatory cytokines, chemokines and growth factors that make it more vulnerable toward tumorigenesis. Salivary cytokines have promising features to be used as biomarkers for screening and outcome prediction in this malignancy. To date, the majority of saliva studies have focused on the levels of these inflammatory proteins comparing HNC patients with healthy individuals. However, changes from pre to post RT-treatment have not been extensively explored due to salivary glands destruction and subsequent xerostomia. Therefore, the main goals of this research project are 1) the evaluation of salivary inflammatory markers and 2) the investigation of salivary proteome before and after the irradiation process, in order to identify potential predictive biomarkers of RT response in HNC. A panel of eight salivary inflammatory markers (IL-4, IL-6, IL-8, IL-10, MCP-1, TNF-α, VEGF, and EGF) was analysed in a group of HNC patients (N=30), pre- and post-RT, and a group of healthy subjects (N=37) as well, using immunoassays based on Multi Analyte Profiling technology (Luminex xMAP). The investigation of the salivary proteome was carried out using liquid chromatography and tandem mass spectrometry technique with SWATH acquisition (LC-MS/MS-SWATH), which consisted of two phases: generation of a peptide spectral library using 10 HNC saliva samples and quantification of 30 individual salivary proteome profiles, selected from the two cohorts of the study. Results concerning the salivary inflammatory markers showed a post-treatment augmentation in multiple cytokines, being the increment of IL-8 and MCP-1 statistically significant (p-value ≤ 0,001 and ≤ 0,0001, respectively). The comparison between the control group and the HNC patients before receiving the RT reported a significant increase of IL-6 levels (p-value ≤ 0,0001), to be associated with the presence of the tumour lesion. Lastly, ROC curves analysis pointed out the strong potential of IL-8 as a predictive biomarker of RT outcomes (AUC= 0.84; p-value= 0.018). Results from the proteomic investigation demonstrated that the salivary proteome varies in saliva of HNC patients undergoing radiotherapy. Comparing pre- and post-treatment conditions a total of 21 proteins results differentially expressed. Besides, analysing the pattern followed by the control subjects and the HNC patients not yet treated, an altered salivary protein profile was detected. Among the salivary markers identified, gene NUCB2 product, gene PPIB product and gene HSPE1 product may be considered as potential predictive biomarkers of RT response, gene LTF product can help to discriminate between HNC cases pre- and post-RT, whereas gene SERPINA3 product and gene AGPAT1 product are related to the presence of HNC. Our data support the hypothesis that screening salivary inflammatory molecules could provide a useful approach to identify biomarkers in this malignancy. Proteomic results need to be validated in a larger cohort of samples before its potential translation into clinical research. These findings may serve as the foundation of studies exploring the use of saliva as a biofluid to monitor treatment outcomes.