Recent clinical observations indicate that female gender is associated with a higher risk of developing torsades de pointes (TdP) cardiac arrhythmia. In this study, we used the Langendorff technique in isolated perfused rabbit hearts and the whole-cell patch-clamp technique in ventricular myocytes to examine the gender difference in TdP incidence and gain insight into the underlying mechanisms. Isolated rabbit hearts were perfused by using the Langendorff technique. TdP was induced by abrupt changes of cycle length (deltaCL) in the presence of Tyrode's solution containing 1 mM 4-aminopyridine (4AP) and 50% reduced Mg2+ and K+ (low K/Mg). The effects of 1 mM 4AP on cardiac potassium currents were characterized by using the patch-clamp technique. Results demonstrated that (a) no significant gender difference was observed in the absolute QT interval before or after 4AP perfusion in the presence of low K/Mg; (b) 4AP caused marked QT prolongation in the ECG; (c) a significantly higher TdP incidence (nine of 12) was found in female hearts compared with male hearts (three of 12; p < 0.05); (d) 1 mM 4AP primarily inhibited Ito, although a slight inhibition of IKr also occurred in low-K/Mg Tyrode's solution. (e) No inhibition of IK1 was observed. (f) No gender difference was found in the potassium current block produced by 4AP. Female gender is associated with a higher incidence of TdP in an experimental isolated heart model and mechanisms subsequent to QT prolongation may contribute to such a gender difference.