The human ether-a-go-go-related gene (hERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the effects of two antipsychotics, tiapride and sulpiride, on hERG channels expressed in Xenopus oocytes and also on delayed rectifier K＋ currents in guinea pig cardiomyocytes. Neither the amplitude of the hERG outward currents measured at the end of the voltage pulse, nor the amplitude of hERG tail currents, showed any concentration-dependent changes with either tiapride or sulpiride (3∼300</SUP>ՌM). However, our findings did show that tiapride increased the potential for half-maximal activation (V1/2) of HERG at 10∼300ՌM, whereas sulpiride increased the maximum conductance (Gmax) at 3, 10 and 100ՌM. In guinea pig ventricular myocytes, bath applications of 100 and 500ՌM tiapride at 36oC blocked rapidly activating delayed rectifier K＋ current (IKr) by 40.3% and 70.0%, respectively. Also, sulpiride at 100 and 500ՌM blocked IKr by 38.9% and 76.5%, respectively. However, neither tiapride nor sulpiride significantly affected the slowly activating delayed rectifier K＋ current (IKs) at the same concentrations. Our findings suggest that the concentrations of the antipsychotics required to evoke a 50% inhibition of IKr are well above the reported therapeutic plasma concentrations of free and total compound.