Oral mucositis (OM) is a very frequent and potentially severe complication experienced by patients receiving chemotherapy and/or radiotherapy, which often leads to significant morbidity and mortality, and decreased quality of life, and is very costly. Despite its severity and prevalence, there is no standard recognised management today. The aim of this open clinical trial is to evaluate the efficacy and compliance of a new spray compound containing sodium hyaluronate (SH) and a pool of collagen precursor amino acids (AAs) combined with sodium hyaluronate (SH) to manage radio/chemotherapy-induced OM. Twenty-seven consecutive patients with OM were treated according to the manufacturers instructions. At time T0 (baseline before intervention), we evaluated the following parameters: (i) pain score (by linear visual analogue scale; 0100) and (ii) severity of OM scored according to WHO Mucositis scale. The treatment efficacy was evaluated on i) pain score, ii) clinical resolution index (CRI) and iii) patient compliance at times T01 (after 2 hours), T1 (after 24 hours), T2 (after 72 hours), T3 (after 7 days) and T4 (after 14 days). Results showed that painful symptoms were significantly reduced after only 2 hours of spray administration compared with baseline measurements (p less than 0.0001; z=-4.541). A progressive reduction of pain through the 2 weeks was also noted (p less than 0.0001). Patient lesions treated with SH-Asbased spray also significantly improved after 72 hours of treatment (p=0.0051; z=-2.803). During the two-week observation, all patients significantly improved from the baseline (p less than 0.0001) and progressively ameliorated their ability to swallow foods and liquids. The compliance of all patients to the product was very good, and at the end of the study there were no adverse effects. The results suggest that the SHAAs-based spray accelerates lesion healing and above all helps to manage mucositis pain, especially in terms of immediate pain relief (after 2 hours from application). Although further randomized controlled studies are recommended, our findings suggest that frequent applications of this spray may offer rapid and effective pain management, aiding faster mucosal wound healing.