Abstract Background Although thyroid dysfunction is a well-known complication of amiodarone treatment, population-based estimates of the short- and long-term incidence of this complication are lacking. In addition, it is not clear whether heart failure (HF) exacerbates this risk. Purpose To examine the short- and long-term incidence of thyroid dysfunction following initiation of amiodarone treatment in patients with and without HF. Methods All Danish residents who initiated amiodarone treatment between 2000–2018 without a history of thyroid dysfunction was identified using nationwide registries. Thyroid dysfunction, defined as a composite of levothyroxine, anti-thyroid medication, or a diagnosis of hypothyroidism, hyperthyroidism, or thyroiditis, was assessed at 1-year follow-up. In a landmark analysis, we estimated the 5-year outcomes with patients grouped according to the cumulated dose (CD) of amiodarone within the first year (regardless of whether treatment duration was shorter than 1 year). The Aalen-Johansen estimator and a cause-specific Cox regression model were applied to compare risk across groups. Results In total, 43,724 patients were identified of whom 16,939 (38%) had a history of HF. Compared to patients without HF, those with HF were at a similar age (71 vs 70 years), more likely men (74% vs 65%), and more often had a history of ventricular tachycardia (19% vs 6%), ischemic heart disease (60% vs 43%), aborted cardiac arrest (8.0% vs. 3.0%), ICD or CRT (30% vs 19%), all p-value <0.01 and less atrial fibrillation (72% vs 73%, p-value 0.02). At 1-year follow-up, the cumulative incidence of thyroid dysfunction was 5.3% in patients with a history of HF vs. 4.2% in patients without HF, adjusted hazard ratio (HR) 1.55 (95% CI, 1.47–1.62), Figure 1. In the landmark analysis, the 5-year cumulative incidences and adjusted HRs of thyroid dysfunction were 5.3% (HR 0.66 [95% CI 0.62–0.70]) in patients with 1-year CD of amiodarone <27.38 g (average daily dose [ADD] <75 mg), 14.0% (reference) for patients with CD 27.38–45.63 g (ADD 75–125 mg), 20.0% (HR 1.28 [95% CI 1.21–1.36]) for patients with CD 45.64–63.88 g (ADD 126–175 mg), and 24.5% (HR 1.39 [95% CI 1.31–1.47]), for patients with CD>63.88 g (ADD >175 mg), (Figure 2). Conclusions In patients who initiated amiodarone treatment, around 5% had evidence of thyroid dysfunction at 1-year follow-up with a slightly higher incidence in those with a history of HF. A dose-response relationship was observed between the 1-year amiodarone cumulative dose and the subsequent 5-year cumulative incidence of thyroid dysfunction. Funding Acknowledgement Type of funding sources: None.