Background: Dose-dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no data to inform on the combination of DD chemotherapy with trastuzumab for patients with HER2-positive disease. Methods: This is a protocol predefined secondary analysis of the randomized phase 3 PANTER trial. Women 65 years old or younger with node-positive or high-risk node negative BC were randomized 1:1 to either tailored according to hematologic nadirs and DD epirubicin/cyclophosphamide (4 cycles) followed by 4 cycles of docetaxel (tDD EC/D) or standard 3-weekly 5-fluorouracil/E/C (3 cycles) and D (3 cycles); Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. In addition, HER2-positive and an equal number of matched for age, treatment group and institution, HER2-negative patients that were enrolled in Swedish sites were enrolled in a predefined study of cardiac safety and underwent echocardiography or MUGA and electrocardiography at baseline and at four and six years of follow-up. The primary endpoint was BC relapse-free survival (BCRFS). Results: There were 342 HER2-positive patients; 335 received at least one dose of trastuzumab, while 29 patients discontinued trastuzumab prematurely. BCRFS was not statistically significantly in favor of tDD EC/D (HR = 0.68, 95% CI 0.37 – 1.27, P= 0.231). Cardiac outcomes after four and six years of follow-up did not differ significantly between HER2-positive and HER2-negative patients, nor between tDD and standard treatment. Conclusions: To our knowledge, these are the only data on combining DD adjuvant chemotherapy and trastuzumab in BC. The combination decreased the risk for BC relapse by 32% compared to standard treatment, a statistically non-significant difference. Its efficacy and safety merit further evaluation as part of both escalation and de-escalation strategies. Clinical trial information: NCT00798070