Background: HER2-targeted therapies are associated with cardiotoxicity, mostly asymptomatic and reversible. The impact of withholding these therapies on breast cancer outcomes is unknown. SAFE-HEaRt trial was the first study to evaluate the safety of HER2-targeted agents in patients with reduced left ventricular ejection fraction (LVEF) receiving concomitant cardioprotective medications and close cardiac monitoring. We report the 3-year follow-up (f/u) results. Methods: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with asymptomatic LVEF 40-49%, were started on beta blockers (ß-blockers) and/or ACE inhibitors/ARBs, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. Results: Patients were accrued from 10/2013 to 12/2017 and median f/u as of 2/7/20 is 37 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. 24 patients were reconsented for long-term f/u. There were 23 evaluable patients (1 lost for f/u). Off study, 2 patients continued treatment with trastuzumab, 3 with trastuzumab and pertuzumab, and 3 with TDM-1 for metastatic disease. 1 of the 2 patients who had developed a CE with symptomatic heart failure (HF) died of progressive oncological disease, and the second had LVEF recovery on cardiac medications after completion of adjuvant HER2-targeted therapy. Almost 5 years later, she had an asymptomatic decline in her LVEF to 35% after deciding to stop her ß-blocker and ARB. Of the remaining 21 patients, 15 had recovery of their LVEF to ≥50%, 9 of whom remain on cardiac medications. 5 patients had stable LVEF 40-49% and remain asymptomatic on cardiac medications. Only 1 patient had symptoms suggestive of HF, with last documented LVEF stable at 45-50%, but she has not sought medical care for the last 15 months since relocating to another country. There were no new CE and no cardiac deaths. Mean LVEF was 45% at baseline, 46% at end of treatment, and 51.5% at long term f/u. Conclusions: Long-term f/u of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is essential for improved patient outcomes. Clinical trial information: NCT04143594.