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Clozapine is an atypical neuroleptic used to manage treatment-resistant schizophrenia which is known to inhibit cardiac hERG/K V 11.1 potassium channels, a pharmacological property associated with increased risk of potentially fatal Torsades de Pointes (TdP) and sudden cardiac death (SCD). Yet, the long-standing clinical practice of clozapine does not show a consistent association with increased incidence of TdP, although SCD is considerably higher among schizophrenic patients than in the general population. Here, we have established the inhibitory profile of clozapine at the seven cardiac ion currents proposed by the ongoing comprehensive in vitro pro-arrhythmia (CiPA) initiative to better predict new drug cardio-safety risk. We found that clozapine inhibited all CiPA currents tested with the following rank order of potency: K V 11.1 > Na V 1.5 (late current) ≈ Ca V 1.2 ≈ Na V 1.5 (peak current) ≈ K V 7.1 > K V 4.3 > K ir 2.1 (outward current) . Half-maximal inhibitory concentrations (IC 50 ) at the repolarizing K V 11.1 and K V 7.1 channels, and at the depolarizing Ca V 1.2 and Na V 1.5 channels fell within a narrow half-log 3-10 µM concentration range, suggesting that mutual compensation could explain the satisfactory arrhythmogenic cardio-safety profile of clozapine. Although the IC 50 values determined herein using an automated patch-clamp (APC) technique are at the higher end of clozapine plasmatic concentrations at target therapeutic doses, this effective antipsychotic appears prone to distribute preferentially into the cardiac tissue, which supports the clinical relevance of our in vitro pharmacological findings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)