Measurement of the QT dispersion (the maximal interlead difference) on the surface electrocardiogram has been suggested for assessing the risk for ventricular arrhythmias and for examining drug effects and their proarrhythmic potential. The acute response of QT dispersion was assessed in 10 healthy subjects receiving disopyramide, which is known to delay repolarization and to prolong global measures thereof. The QRS, JT, and QT intervals and their dispersion were assessed at spontaneous rhythm and at atrial pacing at baseline and after an intravenous injection of disopyramide 2 mg/kg over 5 minutes. The short-term (within 30 minutes) and long-term (> or = 2 weeks) variabilities of the QT interval and the QT dispersion, expressed as the coefficient of variation, were also analyzed. At spontaneous rhythm the group average QT interval was between 369 and 375 msec, and the QT dispersion was between 33 and 37 msec; both were relatively stable over time. All subjects responded homogeneously to disopyramide with a significant QT prolongation (p < 0.001), but no consistent response of the QT dispersion was observed. This discrepancy reflects the significant difference in time-dependent variability with a coefficient of variation of spontaneous, paced, and heart rate-corrected QT dispersion between 25% and 42%, 8-42 times greater than the corresponding values of 1-4% for the QT intervals. The individual response of the QT dispersion to drug challenge should therefore be interpreted with caution. Furthermore and as a consequence, QT dispersion is less sensitive for assessing drug effects on ventricular depolarization and repolarization than the QT interval.