We recently published 2-year results of the prospective, randomized IMRT-MC2 trial, showing non-inferior local control and cosmesis in breast cancer patients after conventionally fractionated intensity-modulated radiotherapy with simultaneously integrated boost (IMRT-SIB), compared to 3D-conformal radiotherapy with sequential boost (3D-CRT-seqB). The present study reports on 2-year quality of life results.Five hundred two patients were enrolled to analyze non-inferiority of IMRT-SIB (50.4 Gy in 1.8 Gy fractions with a 64.4 Gy SIB to the tumor bed in 2.3 Gy fractions) to 3D-CRT-seqB (50.4 Gy in 1.8 Gy fractions, followed by a sequential boost of 16 Gy in 2 Gy fractions). For quality of life (QoL) assessment, patients completed the QLQ-C30 (15 items) and QLQ-BR23 (8 items) questionnaires at baseline and 6 weeks and 2 years after radiotherapy. Comparisons between treatment groups were made at 6 weeks and 2 years after radiotherapy, using Mann-Whitney U-test. The Friedmann test was used to compare QoL at different time points during follow-up (baseline, 6 weeks and 2 years after radiotherapy) and to detect significant changes of QoL over all time points.After six weeks and two years, 237 and 212 QoL questionnaires (94 % and 84 %) were available in the IMRT group, 231 and 210 (93 % and 84 %) in the control group, respectively. The only significant difference of QoL scores between the IMRT-SIB and the 3-D-CRT-seqB group was seen 6 weeks after radiotherapy for pain (22.3 points for IMRT vs. 27.0 points for 3D-CRT-seqB; P = 0.033; r = 0.102) and for arm symptoms (18.1 points for IMRT vs. 23.6 points for 3D-CRT-seqB; P = 0.013; r = 0.118), both favoring IMRT. Looking at changes after two years compared to baseline, both arms showed significant improvement in global score (IMRT: P = 0.009, r = 0.021; 3D-CRT: P = 0.001, r = 0.028) with slight deterioration on the role (IMRT: P = 0.008, r = 0.021; 3-D-CRT: P = 0.001, r = 0.038) and social functioning (IMRT: P = 0.013, r = 0.021; 3D-CRT: P = 0.001, r = 0.033) as well as the future perspectives scale (IMRT: P = 0.003, r = 0.026; 3D-CRT: P = 0.0034, r = 0.020).This is the first randomized phase III trial demonstrating that simultaneously integrated boost irradiation was associated with slightly superior quality of life compared to conventional sequential boost irradiation. These findings further support the widely clinical implementation of SIB in adjuvant breast cancer treatment. NCT01322854.