The performance of normal subjects during radionuclide ventriculography has been related to age, but the combined effects of age and sex on exercise ventricular function are not well described. We studied 55 normal volunteers, 27 men (age = 30 +/- 10 years) and 28 women (age = 33 +/- 14 years), free of chest pain syndromes, during supine rest/exercise radionuclide ventriculography performed to fatigue. Resting left ventricular ejection fraction did not differ between male and female subjects (64 +/- 5.4 vs 64 +/- 6.1; p = NS). Both the peak left ventricular ejection fraction (78 +/- 4.4 vs 72 +/- 9.2; p less than 0.001) and the change in ejection fraction with exercise (14 +/- 4.0 vs 7.9 +/- 7.0; p less than 0.001) were significantly greater in men compared to respective values in women. Regression analysis showed that sex (r = 0.51; p less than 0.001) but not age (r = -0.18; p = 0.19) was a significant predictor of change in ejection fraction with exercise. Data on left ventricular volume response to exercise, available in 43 subjects, revealed that men had a greater percentage of decline in end-systolic volume with exercise than women (-47 +/- 15 vs -24 +/- 26; p less than 0.001). It is concluded that sex exerts a significant influence on normal left ventricular response to fatigue-limited supine exercise and that the gender difference is mediated, in part, by left ventricular end-systolic volume response to exercise.