Background: Significant improvement in disease-free and overall survival has been established with the addition of H to adjuvant chemotherapy. However, H may increase risk of cardiac dysfunction (CD) and warrants long-term evaluation. Methods: N9831 compared adjuvant doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (T) (Arm A) vs. ACàTàH (Arm B) or ACàTHàH (Arm C) in operable HER2+ breast cancer. Cumulative incidence of cardiac events (CE) (symptomatic CHF and definite/probable cardiac death) and left ventricular ejection fraction (LVEF) assessed by MUGA/ECHO were evaluated in women who proceeded to post-AC therapy. Risk factors for H-related CD were identified by Cox regression models. Results: 977 women with clinical and LVEF data beyond 5 years (yr) from study enrollment were included (Arm A=304; Arm B=346 and Arm C=327); median follow up: 6.6 yr. Median age: 50 yr (range, 22–82). Median LVEF at 6 yr: 61% (Arm A); 61% (Arm B) and 60% (Arm C). Absolute median LVEF decrease from baseline: 3.0% (Arm A), 2.5% (Arm B) and 3.0% (Arm C). 6-yr cumulative incidence of CE: 0.6%, 2.8% and 3.4% in Arms A, B and C (minimal difference from CE at 3 yr: 0.5%, 2.6% and 3.4%). Suspected cardiac deaths: 4 (Arm A); 1 (Arm B); 1 (Arm C). There was a statistically significant increase in risk of CE in Arms B (HR 2.6; 95% CI: 1.1–6.2) and C (HR 3.4; 95% CI: 1.4–8.0) vs A (P = 0.019). Associated with increased risk of CE in Arms B and C were age > 60 yr (HR 3.2; 95%: CI 1.5-6.8, P = 0.0019), LVEF (50-55%) at registration (HR 3.3; 95% CI: 1.1-9.6, P = 0.030), and use of antihypertensive medications (HR 2.3; 95% CI: 1.2-4.4, P=0.015). Race (P = 0.318) and BMI 25-29.9 (P = 0.1038) and >30 (P = 0.0735) were nonsignificant risk factors. Conclusions: 6-yr cumulative incidence of CE was higher by 2.8% in the H-containing arms vs control arm. We noted minimal difference in the cumulative incidence of CE beyond 3-yr (Perez, JCO 2008), suggesting that late development of CE with H is infrequent. Hence, H (in context of anthracycline and taxane-based therapy) continues to have a favorable benefit-risk ratio (5-yr absolute OS benefit: 3.5%; DFS benefit: 12.7%). Older age, lower registration LVEF and antihypertensive medication use were predictive of increased risk of CD with H.