Background: The primary aim was comparing acute toxicity between conventional fractionated radiation therapy (CF-RT) and hypofractionated radiation therapy (HF-RT) for patients undergoing breast-conserving surgery or mastectomy with breast or chest wall and regional nodal irradiation (RNI). The secondary endpoints were acute and subacute toxicity, cosmesis, quality of life, and lymphedema features. Methods: Unblinded randomized trial with total of 86 patients treated with CF-RT (n = 33; 50 Gy/25 fractions ± sequential boost [10 Gy/5 fractions]) versus HF-RT (n = 53; 40 Gy/15 fractions ± concomitant boost [8 Gy/15 fractions]). Toxic effects and cosmesis evaluation used the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE) and the Harvard/NSABP/RTOG scale. Patients-reported QoL was determined using European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and the breast cancer-specific supplementary questionnaire (QLQ-BR23). Lymphedema determination compared volume differences between the affected and contralateral arms using the Casley-Smith volume formula. Results: Grade 2 and grade 3 skin rash dermatitis were lower with HF-RT than with CF-RT (28% vs. 52%, 0% vs. 6%; p = 0.022, respectively). HF-RT vs. CF-RT had lower rate of grade 2 hyperpigmentation (23% vs. 55%; p = 0.005). No differences in overall rates of any physician-assessed grade 2 or higher and grade 3 or higher acute toxicity between HF-RT vs. CF-RT were registered. There was no statistical difference between the CF-RT and the HF-RT regarding cosmesis, lymphedema rate (13% vs. 12% HF-RT vs. CF-RT; p = 1.000, respectively), and functional and symptom scales during irradiation and after six months of treatment. Conclusions: HF-RT showed lower rates of acute toxicity, with no changes in quality-of-life outcomes. Clinical trial information: NCT04015531.