K+ channels are key components of the primary and secondary basolateral Cl- pump systems, which are important for secretion from the salivary glands. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. We studied the effects of paroxetine on a human K+ channel, human ether-a-go-go-related gene (hERG), expressed in Xenopus oocytes and on action potential in guinea pig ventricular myocytes. The hERG encodes the pore-forming subunits of the rapidly-activating delayed rectifier K+ channel (IKr) in the heart. Mutations in hERG reduce IKr and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to lifethreatening arrhythmias. Paroxetine induced concentrationdependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The inhibition was concentration-dependent and time-dependent, but voltageindependent during each voltage pulse. In guinea pig ventricular myocytes held at 36℃, treatment with 0.4 μM paroxetine for 5 min decreased the action potential duration at 90% of repolarization (APD90) by 4.3%. Our results suggest that paroxetine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects of clinical administration of paroxetine.