Loperamide is a μ-opioid receptor agonist commonly used to treat diarrhea and often available as an over-the-counter medication. Recently, numerous reports of QRS widening accompanied by dramatic QT interval prolongation, torsades de pointe arrhythmia, and death have been reported in opioid abusers consuming large amounts of the drug to produce euphoria or prevent opiate withdrawal. The present study was undertaken to determine the mechanisms of this cardiotoxicity. Using whole-cell patch clamp electrophysiology, we tested loperamide on the cloned human cardiac sodium channel (Na v 1.5) and the two main repolarizing cardiac K+ channels cloned from the human heart: K v LQT1/minK and the human ether-a-go-go-related gene (hERG) channel. Loperamide inhibited Na v 1.5 with IC 50 values of 297 and 239 nM at holding potentials of −90 and −70 mV, respectively. Loperamide was weakly active on K v LQT1/minK producing 17 and 65 % inhibition at concentrations of 1 and 10 μM, respectively. Conversely, loperamide was found to be a very high affinity inhibitor of the hERG channel with an IC 50 value of 89 nM at room temperature and 33 nM when measured at physiological temperature. The QRS and QT interval prolongation and the attending arrhythmias, produced by loperamide, derive from high affinity inhibition of Na v 1.5 and especially hERG. Since the drug has been widely available and safely used as directed for many years, we believe that the potent inhibition loperamide possesses for cardiac ion channels has only been uncovered because of the excessive misuse of the drug as a consequence of the recent opioid abuse epidemic.