Abstract Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel following epirubicin plus cyclophosphamide (EC) in patients with HER2 positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Methods Patients received every three week treatment with 4 cycles of EC (90/600 mg/m2 ) followed by 4 cycles of docetaxel (100 mg/m2 ). Targeted therapy with standard dose trastuzumab plus bevacizumab 15 mg/kg was given for a total of one year. Co-primary endpoints were 1) rate of cardiac events (CE) in all patients defined as clinical CHF with a significant decrease in left ventricular ejection fraction (LVEF) or cardiac deaths and 2) pathological complete response (pCR) in both breast and nodes in the neoadjuvant cohort. An independent Cardiac Review Panel determined whether criteria for a cardiac event were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, four (4%; 95% CI, 1.1-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34-59). Five-year RFS and OS for all patients was 79.9% and 90.8%. Conclusions The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although pCR percentage is comparable to chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.