Patients with the Romano-Ward inherited long QT syndrome have an incompletely defined cardiac sympathetic system abnormality, and exhibit ventricular arrhythmias during exercise, fear and anxiety. Treadmill and bicycle exercise were used to modulate cardiac autonomic activity in 27 Romano-Ward subjects and 27 normal controls. The heart rate, and the QT, QTc and QT/QS2 (ratio of electrical to mechanical systole) intervals were compared. Subjects with long QT were compared with normals. Those with a long QT interval had the following results: similar resting heart rates; lower rates during moderate (151.6 vs 169.6 beats/min, p = 0.04) and maximal (155.9 vs 182.1 beats/min, p = less than 0.001) exercise; an abnormal QT cycle-length relationship, with failure of the QT to shorten normally with increasing heart rate; an increase in QTc versus a decrease in normals; supine rest QT/QS2 ratio of 1.12 vs 0.93, p = 0.001; and an exercise QT/QS2 that increased by 30%, from 1.12 at rest to 1.45, versus 15%, in normals, from 0.93 to 1.07, p = 0.001. The lower heart rates and excessively prolonged QT/QS2 ratios during exercise further support an abnormality of, or abnormal cardiac response to, sympathetic activity. A QT/QS2 greater than 1.0 at rest, an exercise QT/QS2 ratio greater than 1.17, and an increase in QTc during moderate exercise may be helpful diagnostic findings in patients with borderline long QTc intervals at rest.