The aim of this double-blind, placebo-controlled, randomized study was to investigate whether topical melatonin administered during radiation therapy could increase the quality of life in patients with primary breast cancer. Patients were followed from the first radiation fraction until 3 weeks after the last. The patients applied 1 g of cream to the irradiated area of the skin twice daily, consisting of either 25 mg/g melatonin and 150 mg/g dimethyl sulfoxide, or a placebo cream. Outcomes were the European Organisation for Research and Treatment of Cancer's quality-of-life questionnaires for breast cancer (QLQ-C30 and QLQ-BR23) on the last day of radiation therapy. As a secondary outcome, we evaluated the breast symptom (BS) scores over the entire duration of the trial in a repeated measures linear model. We included 65 patients and had 17 drop-outs, thus totaling 26 and 22 patients in the melatonin and placebo groups, respectively. BS scores on the last day of radiation did not differ between groups (p = .333). However, the linear model analyzing BS for the entire duration showed that melatonin significantly decreased the symptoms (p = .001). There was no difference in the BS score on the last day of radiation, however, we found that the patients in the melatonin group had significantly lower BS scores over the entire duration of the trial.