Gender differences in the corrected QT interval have been noted since Bazett's initial description during the 1920s. The mechanism of this gender difference is unknown, and this study was undertaken to evaluate potential autonomic and menstrual cycle effects on the QT interval. The study population consisted of a healthy volunteer sample of 23 women and 20 men. Twelve-lead electrocardiographic determinations were made at rest and following double autonomic blockade (with atropine and propranolol) during the menstrual, follicular, and luteal phases of the menstrual cycle. Men were studied during 3 separate visits as controls. The corrected QT interval at baseline tended to be longer in women than men (421 +/- 16 ms vs 414 +/- 15 ms: p <0.07). Following double autonomic blockade, the corrected QT interval increased to 439 +/- 11 ms: p <0.001). However, the gender difference in corrected QT interval was unchanged (443 +/- 15 ms vs 437 +/- 12 ms). At baseline, there was no significant difference in the corrected QT interval among the 3 phases of the menstrual cycle (421 +/- 10, 423 +/- 18, and 420 +/- 18 in the menstrual, follicular, and luteal phases, respectively) and the corrected QT interval was longer in women than men at each visit. Following double autonomic blockade, the corrected QT interval in women was shorter in the luteal phase (438 +/- 16 ms) versus the menstrual (446 +/- 15 ms) or the follicular phase (444 +/- 13 ms; p <0.05). However, this difference, which was not present at baseline, does not appear to be responsible for the gender difference in the QT interval at rest. In conclusion, our results confirm that the corrected QT interval tends to be longer in women than men. Differences in autonomic tone and menstrual cycle variability in the corrected QT in women at rest do not appear to be responsible for the gender differences in the QT interval. The mechanism responsible for the longer QT interval in women remains to be defined.