Background: Anthracyclines have activity against soft-tissue sarcomas (STS), however the risk of cumulative cardiotoxicity can limit their clinical benefit. Recently, the activity of T and D in the treatment of pts with LMS or LPS, after failure of previous tx including anthracyclines, was compared in a phase 3 study (ET743-SAR-3007, Demetri et al, 2015, JCO; 62.4734). Here we report cardiac–related adverse events (AEs) observed in the study. Methods: In this study, 577 pts were randomized 2:1 to receive treatment with T or D every 3 weeks. Data regarding previous anthracycline exposure, medical history and concomitant medications, as well as baseline and end-of-treatment (EOT) left ventricular ejection fraction (LVEF) assessments, and adverse events were collected. Multivariate analysis for risk of LVEF decline on treatment evaluated cumulative anthracycline dose (CAD), LVEF at study entry, a history of cardiac disorder (HCD) and patient age. Results: Median CAD was 241 mg/m2 [D] vs. 270 mg/m2[T], with median times from last anthracycline dose to randomization of 5.9 months [D] vs. 6.9 months [T]. At baseline, 20.3% [D] vs. 24.6% [T] pts were ≥ 65 yrs, 24.4% [D] vs. 28.8% [T] pts reported HCD , 35.5% [D] vs. 45.5% [T] utilized cardiac medication, and 14.0% [D] vs. 12.7% [T] had LVEF ≤ LLN. “Cardiac Disorders” of any grade on study were reported by 14.5% [D] vs. 15.1% [T] pts, most frequently arrhythmias (7.0% [D] vs. 9.5% [T]). “Myocardial disorders” (0% [D] vs. 1.6% [T]) and heart failure (0.6% [D] vs. 2.9% [T]) were also reported. One drug-related death due to “cardiac disorder” was reported in T arm. Baseline and EOT LVEF assessments were obtained in 58.1% [D] and 66.4% [T] of pts; LVEF declines ( ≥ 15%, or ≥ 5% and < LLN) were observed in 11.0% [D] vs. 13.5% [T]. These pts received a median of 2 vs. 8.5 cycles of D vs. T, respectively. A multivariate analysis identified CAD ≥ 300 mg/m2, abnormal LVEF at baseline, a HCD, and age ≥ 65 yrs as independent predictors of LVEF decline. Conclusions: Pts with STS are at risk of cardiac events after prior treatment with anthracyclines; cardiac monitoring should be considered based on age, CAD, HCD, and LVEF. Clinical trial information: NCT01343277