The primary goal of this investigation was to describe the effect of terfenadine on the QT interval corrected for heart rate (QTc) of the scalar electrocardiogram (ECG). The design was double-blind, four-period crossover, dose escalation, which involved 28 normal healthy volunteers and 28 patients with stable cardiovascular disease. At baseline, the normal subjects had a mean QTc interval of 407 msec, whereas the patients with cardiovascular disease had a mean QTc interval of 417 msec (p < 0.01). The largest increase in mean QTc on terfenadine was 24 msec in a normal subject and 28 msec in a patient with cardiovascular disease. The longest average QTc observed was 449 msec and 501 msec in any normal subject and patient with cardiovascular disease, respectively. Compared to baseline, terfenadine 60 mg twice daily is associated with a QTc increase of 6 msec in normal subjects and a 12 msec increase in patients with cardiovascular disease (p < 0.01 vs baseline; p > 0.05 when the two populations were compared). Although the QTc increases from baseline are statistically significant, the magnitude of the spontaneous variability in QTc in the same patients is much greater. Because 40 ECGs were obtained while taking placebo in each participant, the spontaneous variability in QTc interval with placebo was also described. Only one of the 28 normal subjects had a mean baseline QTc ≥440 msec, yet 14 of the 28 normal subjects had at least one of the 40 placebo ECGs with a QTc ≥440 msec. The 28 patients with cardiovascular disease had a mean QTc at baseline of 417 msec; yet 20 of 28 had at least one ECG on placebo with a QTc interval ≥440 msec. On the average, the QTc fluctuated 56 msec in each patient during placebo administration. From the observed placebo variability, we calculated that an increase in QTc of ≥35 msec while receiving drug therapy is likely to represent a drug effect at the 95% confidence interval.