Abstract Background This study was an open-label, 2-arms, monocentric, randomized clinical trial comparing Xonrid®, a topical medical device, versus standard of care (SOC) in preventing and treating acute radiation dermatitis (ARD) in Head and Neck Cancer (HNC) and Breast Cancer (BC) patients undergoing radiotherapy (RT). Methods Eligible HNC and BC patients were randomized 1:1 to receive Xonrid® + SOC or SOC during RT. Patients were instructed to apply Xonrid® on the irradiated area three times daily, starting on the first day of RT and until 2 weeks after RT completion or until the development of grade ≥ 3 skin toxicity. The primary endpoint was to evaluate the proportion of patients who developed an ARD grade < 2 at the 5th week in both groups. Secondary endpoints were median time to grade 2 (G2) skin toxicity onset; changes in skin erythema and pigmentation and trans-epidermal water loss (TEWL); patient-reported skin symptoms. All patients were evaluated at baseline, weekly during RT and 2 weeks after treatment completion. The evaluation included: clinical toxicity assessment; reflectance spectrometry (RS) and TEWL examination; measurement of patients’ quality of life (QoL) through Skindex-16 questionnaire. Results Eighty patients (40 for each cancer site) were enrolled between June 2017 and July 2018. Groups were well balanced for population characteristics. All BC patients underwent 3-Dimensional Conformal RT (3D-CRT) whereas HNC patients underwent Volumetric-Modulated Arc Therapy (VMAT). At week 5 the proportion of BC patients who did not exhibit G2 ARD was higher in Xonrid® + SOC group (p = 0.091). In the same group the onset time of G2 ARD was significantly longer than in SOC-alone group (p < 0.0491). For HNC groups there was a similar trend, but it did not reach statistical significance. For both cancer sites, patients’ QoL, measured by the Skindex-16 score, was always lower in the Xonrid® + SOC group. Conclusion Despite the failure to achieve the primary endpoint, this study suggests that Xonrid® may represent a valid medical device in the prevention and treatment of ARD at least in BC patients, delaying time to develop skin toxicity and reducing the proportion of patients who experienced G2 ARD during RT treatment and 2 weeks later. Trial registration The study was approved by the Ethical Committee of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT 52/14 - NCT02261181). Registered on ClinicalTrial.gov on 21st August 2017.