Purpose <p>Radiation-induced dermatitis (RID) is a common adverse effect of adjuvant radiotherapy in patients with breast cancer, often leading to discomfort and reduced quality of life. Hyperbaric oxygen therapy (HBOT) has been proposed as a potential intervention to mitigate RID, but its efficacy remains uncertain. This pilot study aimed to assess the feasibility, safety, and preliminary efficacy of HBOT in reducing RID severity.</p> Methods <p>This single-institution, randomized, controlled pilot study included 30 patients undergoing adjuvant radiotherapy for breast cancer. Participants were assigned to either HBOT (100% oxygen at 1.5 atmospheres absolute, 30 min per session, three times per week, for 7 weeks) or standard care. The primary outcome was to determine whether HBOT reduces the incidence of grade 2 or higher RID, based on Radiation Therapy Oncology Group criteria. Secondary outcomes included the Skindex-29, Catterall Skin Scoring Profile, Numeric Rating Scale (NRS), and EORTC QLQ Core Questionnaire-C30 scores.</p> Results <p>Twenty-five patients completed the study. The incidence of grade 2 or higher RID was 73.3% in both the HBOT and control groups, with no significant difference (<i>p</i> = 0.700). No statistically significant differences were observed in primary or secondary endpoints. Trends toward lower skin-related discomfort and improved patient-reported outcomes in the HBOT group were noted but did not reach statistical significance. HBOT was well tolerated, with no serious adverse events reported.</p> Conclusion <p>This pilot study did not demonstrate a significant reduction in RID severity with HBOT. However, the therapy was safe and well tolerated, with potential benefits in patient comfort and quality of life. Larger trials with optimized HBOT protocols are needed to clarify its role in RID management.</p> <p>Trial Registration Number and the date of registration: NCT06158347 (28/11/2023) and KCT0009847 (15/10/2024)</p>