The purpose of this study was to determine the effects of quinidine and mexiletine on the adaptation of ventricular refractoriness to a change in heart rate. The ventricular effective refractory period was measured at a basic drive cycle length of 500 msec with basic drive train durations of two beats, eight beats, 20 beats and 3 minutes. The ventricular refractory periods were measured in the baseline state and after oral treatment with quinidine or mexiletine in 20 subjects each. In the baseline state, there was progressive shortening of the ventricular refractory period as the drive train duration increased from two beats to 3 minutes. Quinidine prolonged refractoriness by 5% (p less than 0.001) at each drive train duration. Mexiletine did not affect the ventricular effective refractory period at any of the drive train durations. In a control group of 20 subjects, there were no significant differences between two determinations of refractoriness at each basic drive train duration. In conclusion, neither quinidine nor mexiletine affect the adaptation of ventricular refractoriness to an increase in rate. Although the ventricular effective refractory period measured with a conventional basic drive train duration of eight beats is often more than 20 msec longer than the actual ventricular effective refractory period measured with a drive train duration of 3 minutes, the effects of quinidine and mexiletine on the conventionally measured ventricular effective refractory period accurately reflect the effects of these drugs on the actual ventricular effective refractory period.