PURPOSE: The effect of hyaluronic acid (Ialugen cream) on acute skin reactions after radiotherapy, was assessed in a randomized, double-blind, placebo-controlled study. MATERIAL AND METHODS: Out of the 152 patients presenting with head and neck, breast or pelvic carcinomas and registered in the study, 134 cases-70 in the Ialugen group (IA) and 64 in the placebo group (PBO)-completed their IA or PBO treatment. At the time of randomisation, these two groups were balanced for sex, age, weight and height. The mean total dose of radiation given during the study was 60.6 +/- 10.9 Gy in the IA group and 64.3 +/- 10.8 Gy in the PBO group (P = 0.47). RESULTS: Acute radio-epithelitis scores were significantly higher in the PBO group than in the IA group, starting from the control at week 3 and throughout the 6 weeks of treatment (P < 0.01 from week 3 to week 7; P < 0.05 at weeks 8 and 10). Likewise, the global efficacy judgement expressed, at the end of treatment, by both the physician and the patient showed a significant difference in favour of Ialugen (P < 0.01 and P < 0.05, respectively). There was no significant difference of tolerance between the IA and PBO treatments (P = 0.18 according to the physician and P = 0.42 from the patient's viewpoint). CONCLUSION: The prophylactic use of a cream with hyaluronic acid is shown to reduce the incidence of high grade radio-epithelitis, suggesting an interesting role of the hyaluronic acid cream as supportive treatment to improve compliance and quality of life in patients undergoing radiation therapy.