To evaluate the effect of hypofractionated radiation therapy (HFRT) of the breast/chest wall and regional nodes on overall survival (OS), disease-free survival (DFS), locoregional control and on treatment-related toxicity in patients with breast cancer and nodal involvement. Two hundred fifty-seven patients treated between October 2009 and June 2011 with hypofractionated locoregional radiation therapy (42 Gy in 15 fractions) were retrospectively reviewed, 51 (19.8%) after breast-conserving surgery and 206 (80.2%) after radical surgery. Patients treated with breast-conserving surgery received a boost dose to the tumor bed (delivered by photons, electrons, or interstitial high-dose-rate brachytherapy). Two hundred fifty-six (99.6%) patients underwent chemotherapy, 209 (81.3%) had hormonal treatment, and 65 (25.3%) had anti-HER2 targeted therapy. The median follow-up time was 64 months (range, 11-88 months). The rates of 5-year OS, DFS, locoregional recurrence (LRR)-free survival, and distant metastasis (DM)-free survival were 86.6%, 84.4%, 93.9%, and 83.1%, respectively. In multivariate analysis (MVA), lymph node ratio >65%, lymphovascular invasion, and negative hormone receptor status predicted for OS, DSF, and DM. T3 to 4 stage was also associated with worse DFS and DM. Finally, for LRR the independent prognostic factors on MVA were N2 to 3 stage and grade 3. Hyperpigmentation was observed in 19.2% of patients, telangiectasia in 12.3%, and fibrosis in 30.7%. Grade ≥2 lymphedema was recorded in 5.8% of cases. During the study follow-up, no cardiac or symptomatic pneumonitis was observed, nor were plexopathy or rib fractures. According to the findings from this retrospective study, HFRT seems to be an acceptable alternative for patients with breast cancer who need regional nodal irradiation. However, prospective randomized trials are necessary to confirm these preliminary results.