Background Signal-averaged ECG is a noninvasive test designed to detect "late potentials." The effects of alterations in autonomic tone on the signal-averaged ECG have not been evaluated systematically.Methods and Results The effects of autonomic stimulation and blockade on the signal-averaged ECG were evaluated in 14 healthy subjects (8 men and 6 women; age, 28.5+-4.8 years) on 2 separate days. The signal-averaged ECG was recorded at baseline and after physiological and pharmacologic beta -adrenergic stimulation (tilt, exercise, and epinephrine and isoproterenol infusions), sequential and combined beta -adrenergic and parasympathetic blockade, and alpha -adrenergic stimulation before and after parasympathetic blockade. Analysis was performed with a bidirectional filter (40-Hz high-pass). Significant changes in the signal-averaged QRS duration from baseline (105.1+-12.0 milliseconds) were noted with tilt (96.8+-8.8 milliseconds), tilt after double blockade (97.5+-9.0 milliseconds), epinephrine (110.5+-11.8 milliseconds), and isoproterenol (99.6+-12.6 milliseconds). Changes in the root-mean-square voltage of the terminal 40 milliseconds and the low-amplitude (<40 microvolts) signal duration paralleled the changes in the QRS duration.Conclusions The signal-averaged ECG does not measure only "fixed" parameters but rather is altered under a variety of physiological and pharmacologic conditions. Upright tilt leads to shortening of the QRS duration before and after autonomic blockade; thus, the decrease in QRS duration with tilt may be related to factors other than changes in autonomic tone. These findings have implications for interpretation of the results of signal-averaged ECG. (Circulation. 1994;89:1656-1664.)