High plasma levels of mono-N-desethylamiodarone (MDEA), an active amiodarone metabolite, may be associated with tissue toxicity in heart failure (patients with heart rhythm disturbances); therefore, a tool that can identify patients for whom therapeutic drug monitoring (TDM) of MDEA is required. This multicenter study aimed to develop a decision tree (DT) model that can identify patients with heart rhythm disturbances at high MDEA concentrations. A multicenter retrospective cohort study was conducted, including 157 adult patients with heart failure who received oral amiodarone treatment. A χ2 automatic interaction-detection algorithm was used to construct a DT model. In the DT analysis, the dependent variable was set as an MDEA trough plasma concentration of ≥0.6 μg/mL during the steady-state period. Explanatory variables were selected as factors with p < 0.05 in multivariate logistic regression analysis. The adjusted odds ratios for the daily dose of amiodarone and body mass index were 1.01 (95% coefficient interval: 1.008-1.021, p<0.001) and 0.91 (95% confidence interval: 0.834-0.988, p=0.025), respectively. For DT analysis, the risk of reaching plasma MDEA concentrations ≥0.6μg/mL was relatively high, combined with a daily dose of amiodarone >100 mg and body mass index ≤22.3 kg/m2 at 69.0% (20/29), and its trend was also detected in the sensitivity analysis. Patients taking a daily amiodarone dose > 100 mg and with a body mass index ≤22.3 kg/m2 warrant TDM implementation for MDEA to minimize the risk of MDEA-induced tissue toxicity.