This was a single-blind, randomized controlled, superiority trial. A computer generated random number sequence to allocate treatments. The objective was to investigate the effects of StrataXRT® versus 10% Glycerine (Sorbolene cream) for preventing and managing radiation dermatitis in patients with head and neck cancer receiving radical radiotherapy (≥50 Gy) with or without chemotherapy/biotherapy. Patients either received treatment 1 (StrataXRT) or Treatment 2 (Sorbolene). Skin toxicity, pain, itching and skin-related quality of life scores were collected for baseline, and up to four weeks post-treatment. Randomization used a computer generated random number list, stratified by schedule for biotherapy. Blocked randomization using permutated block sizes of four and six was performed. A total of 197 patients were randomized into the study. Skin toxicity was dependent on the treatment group with StrataXRT patients experiencing lower mean skin toxicity at the end of the radiation treatment (P=0.002). At the end of treatment, the StrataXRT arm had a lower percentage of grade 2 (80%) and grade 3 (28%) skin toxicity compared to the sorbolene arm (91% and 45% respectively). After adjustment for Cetuximab, the StrataXRT arm had a 12% lower risk of experiencing grade 2 skin toxicity (RRR=0.876, 95% CI: 0.778–0.987, P=0.031); and a 36% lower risk of experiencing grade 3 skin toxicity (RRR=0.648, 95% CI: 0.442–0.947, P=0.025). Cox regression analysis showed that patients receiving StrataXRT had a 41.0% and 49.4% reduced risks of developing grade 2 and 3 skin toxicity respectively throughout treatment compared to the Sorbolene arm. Patients in the StrataXRT arm generally reported better scores (lower pain and itching, and better quality of life) compared to the Sorbolene arm, these findings however did not reach statistical significance. No treatment interruptions and adverse events related to study products were reported in either arm. StrataXRT is effective for preventing, and delaying the development of grade 2 and 3 skin toxicity