The EORTC 22922/10925 trial randomly compares irradiation or no irradiation of the internal mammary and medio supraclavicular (IM-MS) nodes for stage I-III breast cancer. We report on the characteristics of 4004 participating patients, aspects of quality assurance and compliance to protocol treatment. The actual population has intermediate-risk disease: 51.8% stage II, 56% positive axillary nodes. The allocated treatment was not followed in 3.2% in the IM-MS irradiation arm versus 2% in the no IM-MS irradiation arm. In the IM-MS arm, there were major deviations for dose in 0.8%, surgery-to-radiotherapy time interval in 3.9% and in overall treatment time in 0.9% cases. Major deviations were found in 7.9% patients in the IM-MS group and in 2% patients in the no IM-MS group. In the final trial analysis, a sensitivity analysis should evaluate the subgroup of patients receiving an optimal treatment to verify the robustness of the results and the true impact of IM-MS irradiation.