Patients with amiodarone-induced thyrotoxicosis (AIT) and severely reduced left ventricular ejection fraction (LVEF) have a high mortality rate that may be reduced by total thyroidectomy. Whether in this subset of patients thyroidectomy should be performed early during thyrotoxicosis or later after restoration of euthyroidism is unsettled.Mortality rates, including peritreatment mortality and 5-year cardiovascular mortality, and predictors of death, evaluated by Cox regression analysis.Retrospective cohort study of 64 consecutive AIT patients selected for total thyroidectomy from 1997 to 2019. Four groups of patients were identified according to serum thyroid hormone concentrations and LVEF: Group 1 (thyrotoxic, LVEF<40%), Group 2 (thyrotoxic, LVEF≥40%), Group 3 (euthyroid, LVEF<40%), Group 4 (euthyroid, LVEF≥40%).Among patients with low LVEF (Groups 1 and 3), mortality was higher in patients undergoing thyroidectomy after restoration of euthyroidism (Group 3) than in those submitted to surgery when still thyrotoxic (Group 1): peritreatment mortality rates were 40% vs 0%, respectively (p=0.048), whereas 5-year cardiovascular mortality rates were 53.3% vs 12.3%, respectively (p=0.081). Exposure to thyrotoxicosis was longer in Group 3 than in Group 1 (112 days, IQR 82.5-140, vs. 76 days, IQR 24.8-88.5, p=0.021). At variance, survival did not differ in patients with LVEF ≥40% submitted to thyroidectomy irrespective of being thyrotoxic (Group 2) or euthyroid (Group 4): in this setting, peritreatment mortality rates were 6.3% vs 4% (p=0.741) and 5-year cardiovascular mortality rates were 12.5% and 20% (p=0.685), respectively. Age (HR 1.104, p=0.029) and duration of exposure to thyrotoxicosis (HR 1.004, p=0.039), but not presurgical serum thyroid hormone concentrations (p=0.577 for free thyroxine, p=0.217 for free triiodothyronine), were independent predictors of death.A prolonged exposure to thyrotoxicosis resulted in an increased mortality in patients with reduced LVEF, which may be reduced by early thyroidectomy.