BACKGROUND: Adverse effects such as fatigue, pain, erythema, nausea and vomiting are commonly known in patients undergoing irradiation (RT) alone or in combination with chemotherapy (RCHT). Patients suffering from these symptoms are limited in their daily life and their quality of life (QOL) is often reduced. As addressed in several trials, acupuncture can cause amelioration of these specific disorders. Especially for pain symptoms, several groups have shown efficacy of acupuncture. To what extent the difference between traditional acupuncture (verum acupuncture) and false acupuncture (sham acupuncture) is in reducing side effects and improvement of QOL is not clear. METHODS/DESIGN: ROSETTA is a prospective randomized phase II trial (version 1.0) to examine the efficacy of traditional acupuncture in patients with RT-related side effects. In the experimental (verum) arm (n = 37) an experienced acupuncture-trained person will treat dedicated acupuncture points. In the control (sham) arm (n = 37) sham acupuncture will be performed to provide a blinded comparison of results. DISCUSSION: This is the first randomized prospective trial to evaluate the effect of traditional acupuncture on RT-related side effects such as fatigue and QOL. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02674646 . Registered on 8 December 2015.