Pilot studies have shown that patients with human epidermal growth factor receptor 2-positive disease have greater risk of relapse and death. The sooner trastuzumab is administered, the greater seems to be the benefit. A delay in the initiation of adjuvant radiotherapy (RT) may result in an increased rate of local recurrence. Since limited published data exist, the aim of our analyses was to evaluate the skin and heart toxicity of concomitant treatment. Between 2003 and 2012, 95 women were treated at our Institute by concomitant therapy for clinical stage I-III invasive breast cancer. Cardiac toxicity was evaluated according to the left ventricular ejection fraction (LVEF) decrease, with a prospective monitoring program. All acute and late toxicities were assessed according to the CTCAE-v3 criteria. At a median follow-up of 4.3 years (range 1.3-10.4), 5 patients developed locoregional relapse and 7 patients developed distant metastases; disease-free survival was 90% and overall survival 97.9%. Overall, skin toxicity ≥ Grade 2 was recorded in 13 patients (13.7%). No dysphagia and esophagitis ≥ Grade 2 were recorded. Cosmetic outcome was excellent in 41 patients (43.2%), good in 39 patients (41.1%), and fair in 10 patients (10.5%). All patients concluded the programmed RT. Among the 58 patients (61.1%) that recorded a LVEF dysfunction, the median decrease from baseline to the end of trastuzumab was 10%, while the median decrease from baseline to the last follow-up was 7% (p = 0.01). In our experience, concomitant trastuzumab and radiation treatment was overall well tolerated.