The recent development of the VEST, an ambulatory radionuclide detector, to measure left ventricular ejection fraction may enhance the detection of ischemia during daily activities in patients with coronary artery disease. The normal range and determinants of ejection fraction responses to stimuli other than physical exercise, however, are not adequately characterized. Therefore, ejection fraction responses to various activities were measured in 18 normal subjects utilizing the VEST. Uniform increases (greater than 5%) in ejection fraction were seen during physical exercise, uniform decreases were seen during cold pressor testing and modest changes (including decreases greater than 5%) were seen in ejection fraction during mental stress, micturition and hyperventilation. Different forms of stress produced significantly different changes in ejection fraction, even when values were controlled for changes in heart rate. Ventricular loading conditions in the form of enhanced blood pressure responses during mental stress may have contributed to the relatively smaller changes in ejection fraction compared with those during exercise. Subjects demonstrating a decrease in ejection fraction during mental stress did not differ from other subjects in hemodynamic reactivity during mental testing but did have evidence of increased parasympathetic tone during cold pressor and bicycle exercise testing. The results reveal that normal ejection fraction response differs among varying physiologic stimuli. These changes are in part related to changes in heart rate and blood pressure; however, other factors, such as neurohumoral regulation, may also play a role. These findings indicate that the patient's activity and the setting in which it occurs must be considered when interpreting ambulatory ejection fraction responses.