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Background: Methadone is associated with ventricular dysrhythmias and sudden death. Serotonin reuptake inhibitors (SRIs) may increase the risk of these events either by inhibiting metabolism of methadone’s proarrhythmic (S)-enantiomer, additive QT interval prolongation, or both. We sought to determine whether certain SRIs were associated with a higher risk of methadone-related ventricular dysrhythmias or sudden death.Methods: We conducted a nested case-control study of Ontario residents receiving methadone between April 1, 1996 and December 31, 2017. Cases, defined as patients who died of sudden cardiac death or were hospitalized with a ventricular dysrhythmia while on methadone, were matched with up to four controls who also received methadone on age, sex, and a disease risk score. We determined the odds ratio (OR) and p-value functions for the association between methadone-related cardiotoxicity and treatment with SRIs known to inhibit metabolism of (S)-methadone (paroxetine, fluvoxamine, sertraline) or prolong the QT interval (citalopram and escitalopram). Patients who were not treated with an SRI served as the reference group.Results: During the study period, we identified 626 cases and 2,299 matched controls. Following multivariable adjustment, we found that recent use of sertraline, fluvoxamine or paroxetine (adjusted OR 1.30; 95% confidence intervals [CI] 0.90–1.86) and citalopram and escitalopram (adjusted OR 1.26; 95% CI 0.97–1.63) were associated with small increases in the risk methadone-related cardiac toxicity, an assertion supported by the corresponding p-value functions.Interpretation: Certain SRIs may be associated with a small increase in cardiac toxicity in methadone-treated patients.