The purpose of this study was to report rates and severities of radiation-related toxicities and analyze disease-control outcomes in patients who have received hypofractionated whole breast radiation (HF) with concurrent trastuzumab with or without pertuzumab. We conducted a retrospective cohort study including women with stage I-III HER2-positive breast cancer who received HF at the University of Pennsylvania between 1/2005 and 5/2018 with concurrent trastuzumab with or without pertuzumab. Fractionation was 266 cGy daily to a total dose of 4256 cGy with or without a sequential tumor bed boost. Eighty patients were included in the cohort with a median follow-up time of 21.44 months. There was one grade 3 acute toxicity (fatigue) and no grade 3 late toxicities. 91% and 25% of patients experienced grade 1-2 acute and late skin reactions, respectively. An excellent-good cosmetic outcome was reported by 74% and 95% of patients and physicians, respectively. No patients experienced tumor recurrences, and the only death was due to a secondary cause. These results suggest that hypofractionated whole breast radiation administered concurrently with anti-HER-2 therapies is efficacious and has acceptable toxicity in early-stage breast cancer patients treated with lumpectomy. Continued follow-up is warranted to evaluate long-term outcomes. © 2019 Wiley Periodicals, Inc.