Purpose: Hydrofilm, a polyurethane-based barrier film, can be used to prevent acute radiation dermatitis (RD) in adjuvant whole-breast irradiation (WBI) for breast cancer. This cost-effective prophylactic measure is currently being recommended to a growing number of patients, yet long-term safety data and its impact on late radiation-induced skin toxicity such as pigmentation changes and fibrosis have not been investigated. Methods: We objectively evaluated patients who were previously enrolled in either of two intrapatient-randomised (lateral versus medial breast halve) controlled trials on the use of Hydrofilm for RD prevention (DRKS00029665; registered on 19 July 2022). Results: Sixty-two patients (47.7% of the initial combined sample size) provided consent for this post-hoc examination, with a median follow-up time (range) of 58 (37–73) months. Following WBI, there was a significant increase in yellow skin tones of the entire breast when compared to baseline measurements before WBI (p < 0.001) and a significant increase of cutis, subcutis, and oedema thickness (p < 0.001, p < 0.001, and p = 0.004, respectively). At follow-up, there were no significant differences in either pigmentation changes or skin fibrosis between the Hydrofilm and standard of care breast halves. Conclusion: These data suggest that Hydrofilm can be safely used in the context of acute RD prevention, without affecting late side effects, supporting its widespread use.