Background: Grapefruit juice causes significant QT prolongation in healthy volunteers and naringenin has been identified as the most potent human ether-a-go-go-related gene (HERG) channel blocker among several dietary flavonoids. The interaction between naringenin and I<sub>Kr</sub>-blocking antiarrhythmic drugs has not been studied. We evaluated the effect of combining naringenin with I<sub>Kr</sub>-inhibiting antiarrhythmic drugs on cardiac I<sub>Kr</sub>. Methods and Results: I<sub>Kr</sub> current was studied by using HERG expressed in Xenopus oocytes, and the two-electrode voltage clamp technique was employed. Antiarrhythmic drugs (azimilide, amiodarone, dofetilide and quinidine) were tested. Experiments were performed at room temperature. Naringenin blocked HERG current dose dependently with an IC<sub>50</sub> of 173.3 ± 3.1 µ M. Naringenin 100 µ M alone inhibited HERG current by 31 ± 6%, and this inhibitory effect was increased with coadministration of 1 or 10 µ M antiarrhythmic drugs. When 100 µ M naringenin was added to antiarrhythmic drugs, greater HERG inhibition was demonstrated, compared to the current inhibition caused by antiarrhythmic drugs alone. Addition of naringenin significantly increased current inhibition (p < 0.05). Conclusions: There is an additive inhibitory effect on HERG current when naringenin is combined with I<sub>Kr</sub>-blocking antiarrhythmic drugs. This additive HERG inhibition could pose an increased risk of arrhythmias by increasing repolarization delay and possible repolarization heterogeneity.