Comparable outcomes between conventional fractionation and moderate hypofractionation (MHF) had been established. The UK FAST and Fast-Forward trials proved the non-inferiority of ultra-hypofractionation (UHF) after conservative breast surgery. This study is a non-inferiority phase III randomized control trial to evaluate UHF compared to the MHF regimen in mastectomy patients (NCT04550910). Material and methods: Female patients above 18 years were randomized to receive chest wall and nodal irradiation with either a weekly UHF regimen (28.5 Gy/5fx/5 weeks) or MHF (40 Gy/15fx/3 weeks). Conformal 3-D or forward intensity-modulated radiotherapy planning was done. The primary endpoints were acute and late toxicity. Patient-reported outcomes (PROMs) were assessed to evaluate shoulder function and brachial plexopathy. Secondary endpoints were loco-regional recurrence (LRR), overall survival (OS), and disease-free survival (DFS). Results: From November 2019 to June 2021, 176 eligible patients were recruited. The median follow-up was 26.73 ± 5.98 months. Only 1.1 % reported G3 acute skin toxicity in both arms. Severe late skin reaction, telangiectasia or fibrosis were not reported. Conclusion: Once weekly UHF regimen is tolerable and non-inferior to MHF regarding toxicity. Large-scale multi-institutional studies and longer follow up are needed for the evaluation of treatment toxicities and survival benefits.