Introduction: Global longitudinal strain (GLS) can predict cancer therapeutics-related cardiac dysfunction (CTRCD) and guide initiation of cardioprotection (CPT) at the time of chemotherapy. No prospective randomized controlled trial (RCT) has identified the impact on LV function in survivors.Hypothesis: GLS-guided CPT provides less cardiac dysfunction in survivors of potentially cardiotoxic chemotherapy, compared with usual care.Methods: In this international (28 sites) multicenter prospective RCT, patients (pts) were included if they were administrated anthracyclines and had another risk factor for HF. They were randomly allocated into undergoing GLS-guided CPT for >12% relative reduction in GLS or EF-guided CPT for >10% absolute reduction of EF. Primary endpoint was the change in EF (ΔEF) from baseline to 3 years by 3D echocardiography.Results: Among 331 pts enrolled, 255 (77%, 60±16 years, 95% women) completed 3-year follow-up (123 in EF-guided group and 132 in GLS-guided). Most had breast cancer (236, 93%), 67 (26%) with hypertension and 32 (13%) with diabetes mellitus. A regimen of anthracycline and trastuzumab was the most common chemotherapy regimen (84%). The baseline LVEF was 61±4% with GLS of 20.7±2.3% in the entire population. CPT was administrated in 18 pts (15%) in EF-guided and 41 (31%) in GLS-guided (p=0.02). Most patients showed recovery in EF and GLS after chemotherapy (Figure). ΔEF was -2.0±4.8 in EF-guided and -1.4±5.4 in GLS-guided (p=0.25), but LVEF at 3 years in EF-guided was lower than that of GLS-guided (58.0±5.6% vs 59±4.9%, p=0.043). Ten pts in EF-guided developed CTRCD, and 6 in GLS-guided (p=0.24).Conclusions: Most of the enrolled pts were taking potentially cardiotoxic chemotherapy for breast cancer. Almost all improved LV function over 3 years, and although GLS-guided CPT was associated with higher EF at 3 years, there was no difference in ΔEF compared with EF-guided surveillance.